Aging in COVID-19: Vulnerability,immunity and intervention

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic was first reported in Wuhan, China in December 2019, moved across the globe at an unprecedented speed, and is having a profound and yet still unfolding health and socioeconomic impacts. SARS-CoV-2, a β-coronavirus, is a highly contagious respiratory pathogen that causes a disease that has been termed the 2019 coronavirus disease (COVID-19). Clinical experience thus far indicates that COVID-19 is highly heterogeneous, ranging from being asymptomatic and mild to severe and causing death. Host factors including age, sex, and comorbid conditions are key determinants of disease severity and progression. Aging itself is a prominent risk factor for severe disease and death from COVID-19. We hypothesize that age-related decline and dysregulation of immune function, i.e., immunosenescence and inflammaging play a major role in contributing to heightened vulnerability to severe COVID-19 outcomes in older adults. Much remains to be learned about the immune responses to SARS-CoV-2 infection. We need to begin partitioning all immunological outcome data by age to better understand disease heterogeneity and aging. Such knowledge is critical not only for understanding of COVID-19 pathogenesis but also for COVID-19 vaccine development.     

Targeting immune dysfunction in aging

Human aging is a multifactorial phenomenon that affects numerous organ systems and cellular processes, with the immune system being one of the most dysregulated. Immunosenescence, the gradual deterioration of the immune system, and inflammaging, a chronic inflammatory state that persists in the elderly, are among the plethora of immune changes that occur during aging. Almost all populations of immune cells change with age in terms of numbers and/or activity. These alterations are in general highly detrimental, resulting in an increased susceptibility to infections, reduced healing abilities, and altered homeostasis that promote the emergence of age-associated diseases such as cancer, diabetes, and other diseases associated with inflammation. Thanks to recent developments, several strategies have been proposed to target central immunological processes or specific immune subpopulations affected by aging. These therapeutic approaches could soon be applied in the clinic to slow down or even reverse specific age-induced immune changes in order to rejuvenate the immune system and prevent or reduce the impact of various diseases. Due to its systemic nature and interconnection with all the other systems in the body, the immune system is an attractive target for aging intervention because relatively targeted modifications to a small set of cells have the potential to improve the health of multiple organ systems. Therefore, anti-aging immune targeting therapies could represent a potent approach for improving healthspan. Here, we review aging changes in the major components of the immune system, we summarize the current immune-targeting therapeutic approaches in the context of aging and discuss the future directions in the field of immune rejuvenation.     

Sialic acid-mediated photochemotherapy enhances infiltration of CD8+ T cells from tumor-draining lymph nodes into tumors of immunosenescent mice

Immunoscenescence plays a key role in the initiation and development of tumors. Furthermore, immunoscenescence also impacts drug delivery and cancer therapeutic efficacy. To reduce the impact of immunosenescence on anti-tumor therapy, this experimental plan aimed to use neutrophils with tumor tropism properties to deliver sialic acid (SA)-modified liposomes into the tumor, kill tumor cells via SA-mediated photochemotherapy, enhance infiltration of neutrophils into the tumor, induce immunogenic death of tumor cells with chemotherapy, enhance infiltration of CD8⁺ T cells into the tumor-draining lymph nodes and tumors of immunosenescent mice, and achieve SA-mediated photochemotherapy. We found that CD8⁺ T cell and neutrophil levels in 16-month-old mice were significantly lower than those in 2- and 8-month-old mice; 16-month-old mice exhibited immunosenescence. The anti-tumor efficacy of SA-mediated non-photochemotherapy declined in 16-month-old mice, and tumors recurred after scabbing. SA-mediated photochemotherapy enhanced tumor infiltration by CD8⁺ T cells and neutrophils, induced crusting and regression of tumors in 8-month-old mice, inhibited metastasis and recurrence of tumors and eliminated the immunosenescence-induced decline in antitumor therapeutic efficacy in 16-month-old mice via the light-heat-chemical-immunity conversion.     

Increased T cell immunosenescence and accelerated maturation phenotypes in older kidney transplant recipients

Older kidney transplant recipients experience increased rates of infection and death, and less rejection, compared with younger patients. However, little is known about immune dysfunction in older compared with younger kidney transplant recipients and whether it is associated with infection. We evaluated T cell phenotypes including maturation, immune senescence, and exhaustion in a novel investigation into differences in older compared with younger patients receiving identical immune suppression regimens.We evaluated PBMC from 60 kidney transplant recipients (23 older and 37 matched younger patients) by multiparameter immune phenotyping. Older kidney transplant recipients demonstrated decreased frequency of naïve CD4+ and CD8+ T cells, and increased frequency of terminally differentiated, immune senescent, and NK T cells expressing KLRG1. There was a trend towards increased frequency of T cell immune senescence in patients experiencing infection in the first year after transplantation, which reached statistical significance in a multivariate analysis.This pilot study reveals immune dysfunction in older compared with younger transplant recipients, and suggests a likely mechanism for increased vulnerability to infection. The ability to assess T cell maturation and immune senescence in transplant recipients offers the potential for risk stratification and customization of immune suppression to prevent infection and rejection after transplantation.     

The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process

A chronic low-grade inflammation is one of the hallmarks of the aging process. This gradually augmenting inflammatory state has been termed inflammaging. Inflammaging is associated with increased myelopoiesis in the bone marrow. This myelopoiesis-biased process increases the generation not only of mature myeloid cells, e.g. monocytes, macrophages, and neutrophils, but also immature myeloid progenitors and myeloid-derived suppressor cells (MDSCs). It is known that the aging process is associated with a significant increase in the presence of MDSCs in the bone marrow, blood, spleen, and peripheral lymph nodes. Consequently, MDSCs will become recruited into inflamed tissues where they suppress acute inflammatory responses and trigger the resolution of inflammation. However, if the perpetrator cannot be eliminated, the long-term presence of MDSCs suppresses the host’s immune defence and increases the susceptibility to infections and tumorigenesis. Chronic immunosuppression also impairs the clearance of waste products and dead cells, impairs energy metabolism, and disturbs tissue proteostasis. This immunosuppressive state is reminiscent of the immunosenescence observed in inflammaging. It seems that proinflammatory changes in tissues with aging stimulate the myelopoietic production of MDSCs which subsequently induces immunosenescence and maintains the chronic inflammaging process. We will briefly describe the functions of MDSCs and then examine in detail how inflammaging enhances the generation MDSCs and how MDSCs are involved in the control of immunosenescence occurring in inflammaging.     

Immunosenescence in rheumatoid arthritis: Use of CD28 negative T cells to predict treatment response

Not many years ago achieving remission in rheumatoid arthritis (RA) was difficult due to lack of effective treatment. With the advent of biologics, remission is very much within reach. But biologics are expensive. And not all patients respond adequately to biologics. Hence it will be useful if we have a marker which predicts response to any disease modifying anti-rheumatic drug (DMARD), whether conventional or biologic. Expansion of CD28-ve T cells is characteristically seen in RA. Both CD28-ve T Cells and RA are believed to be linked to immunosenescence. The available evidence is suggestive of an intimate relationship between RA and clonal expansion of CD28-ve T cells. Newer biomarkers are constantly being looked at and CD28-ve T cells is one of them. In this review the relationship between immune disorders like RA and immunosenescence and significance of CD28-ve T cells in RA is discussed.     

Dietary supplementation of milk fermented with probiotic Lactobacillus fermentum enhances systemic immune response and antioxidant capacity in aging mice

Although probiotics are known to enhance the host immune response, their roles in modulating immunosenescence, resisting infection, and improving redox homeostasis during aging remain unclear. Therefore, the present study was devised in aging mice to assess the antiimmunosenescence potential from the consumption of milk that is fermented with probiotic Lactobacillus fermentum MTCC 5898 (LF). We hypothesized that probiotic supplementation would boost immunity, improve antioxidant capacity, and resist severity of pathogenic infection in aging mice. To test this hypothesis, during a trial period of 2 months, 16-month-old male Swiss mice were kept on 3 experimental diets: basal diet (BD), BD supplemented with skim milk, and BD supplemented with probiotic LF-fermented milk. A concurrent analysis of several immunosenescence markers that include neutrophil functions, interleukins profile, inflammation and antibody responses in the intestine as well as analysis of antioxidant enzymes in the liver and red blood cells was performed. Neutrophil respiratory burst enzymes and phagocytosis increased significantly in probiotic LF-fed groups, whereas no exacerbation in plasma levels of monocyte chemotactic protein 1 and tumor necrosis factor α was observed. Splenocytes registered increased interferon-γ but decreased interleukin 4 and interleukin 10 production, whereas humoral antibodies registered decreases in immunoglobulin G1 (IgG1)/IgG2a ratio and IgE levels in the probiotic-fed groups. Antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in LF-fed groups showed increased activities, which were more pronounced in the liver than in red blood cell. An Escherichia coli–based infection model in aging mice was also designed to validate the protective attributes of LF. Administration of probiotic LF significantly reduced E coli population in organs (intestine, liver, spleen, and peritoneal fluid), as compared with control groups, by enhancing E coli–specific antibodies and inflammatory proteins. Based on these results, it appears that LF supplementation alleviated immunosenescence, enhanced antioxidant enzyme activities, and resisted E coli infection in aging mice; thereby, signifying its potential in augmenting healthy aging.     

Can exercise-related improvements in immunity influence cancer prevention and prognosis in the elderly?

Cancer incidence increases with advancing age. Over 60% of new cancers and 70% of cancer deaths occur in individuals aged 65 years or older. One factor that may contribute to this is immunosenescence – a canopy term that is used to describe age-related declines in the normal functioning of the immune system. There are multiple age-related deficits in both the innate and adaptive systems that may play a role in the increased incidence of cancer. These include decreased NK-cell function, impaired antigen uptake and presentation by monocytes and dendritic cells, an increase in ‘inflammaging’, a decline in the number of naïve T-cells able to respond to evolving tumor cells, and an increase in functionally exhausted senescent cells. There is consensus that habitual physical exercise can offer protection against certain types of cancer; however the evidence linking immunological mechanisms, exercise, and reduced cancer risk remain tentative. Multiple studies published over the last two decades suggest that exercise can mitigate the deleterious effects of age on immune function, thus increasing anti-cancer immunity. The potential ameliorative effect of exercise on these mechanisms include evidence that physical activity is able to stimulate greater NK-cell activity, enhance antigen-presentation, reduce inflammation, and prevent senescent cell accumulation in the elderly. Here we discuss the role played by the immune system in preventing and controlling cancer and how aging may retard these anti-cancer mechanisms. We also propose a pathway by which exercise-induced alterations in immunosenescence may decrease the incidence of cancer and help improve prognosis in cancer patients.     

核因子-κB调控老年大鼠脾淋巴细胞凋亡及淫羊藿总黄酮对其影响

目的探讨核因子-κB（nuclearfactor—kappaB，NF-κB）对老年大鼠脾淋巴细胞凋亡的调控作用及淫羊藿总黄酮（epimedium total flaonoids，EF）对老年大鼠脾淋巴细胞凋亡的调控作用是否通过NF—κB实现。方法分别给予老年大鼠模型NF-κB抑制剂二硫代氨基甲酸吡咯烷（PDTC）和EF干预，提取大鼠脾淋巴细胞，用流式细胞仪检测细胞凋亡，Westem blot检测P65蛋白表达，电泳迁移率（electrophoretic mobility shift assay，EMSA）检测NF-κB的活性。结果老年大鼠脾淋巴细胞凋亡率比青年大鼠高（P〈0．01），PDTC使老年大鼠的凋亡率更高，而EF使老年大鼠的凋亡率降低，与老年组相比有显着性差异（P〈0．05），且EF能拮抗PDTC诱导老年大鼠胆淋巴细胞凋亡。与青年大鼠相比老年大鼠脾淋巴细胞P65蛋白表达显著下调（P〈0．01），而使用EF的老年大鼠组P65蛋白表达明显上调，表明EF诱导P65高表达。老年大鼠脾淋巴细胞NF-κB的活性弱于青年大鼠（P〈0．01），而PDTC处理组的NF—κB活性最低与老年大鼠组相比差异明显（P〈0．01），EF干预组的NF-κB的活性最强，与老年大鼠组相比差异非常显著（P〈0．01）。相关分析表明，淋巴细胞NF—κB活性与细胞凋亡率呈负相关（r=-0．57，P〈0．01）。结论NF-κB通过抑制淋巴细胞凋亡而参与老年大鼠免疫衰老调控过程；EF可能通过提高NF-κB的活性和诱导P65高表达来抑制淋巴细胞凋亡从而延缓免疫衰老进程。