Immunosenescence encompasses multiple age-related adaptations that result in increased susceptibility to infections, chronic inflammatory disorders, and higher mortality risk. Macrophages are key innate cells implicated in inflammatory responses and tissue homeostasis, functions progressively compromised by aging. This process coincides with declining mitochondrial physiology, whose integrity is required to sustain and orchestrate immune responses. Indeed, multiple insults observed in aged macrophages have been implied as drivers of mitochondrial dysfunction, but how this translates into impaired immune function remains sparsely explored. This review provides a perspective on recent studies elucidating the underlying mechanisms linking dysregulated mitochondria homeostasis to immune function in aged macrophages. Genomic stress alongside defective mitochondrial turnover accounted for the progressive accumulation of damaged mitochondria in aged macrophages, thus resulting in a higher susceptibility to excessive mitochondrial DNA (mtDNA) leakage and reactive oxygen species (ROS) production. Increased levels of these mitochondrial products following infection were demonstrated to contribute to exacerbated inflammatory responses mediated by overstimulation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and cyclic GMP-ATP synthase (cGAS)-stimulator of interferon genes (STING) pathways. While these mechanisms are not fully elucidated, the present evidence provides a promising area to be explored and a renewed perspective of potential therapeutic targets for immunological dysfunction.

Changes occurring in the immune system along the ageing process increase the risk of infection, susceptibility to tumor development, and autoimmunity. Interventions such as physical exercise, supplements, and probiotics have been proposed in order to circumvent these conditions. Vitamin D supplementation could contribute to the immune system homeostasis in older adults since a large proportion of this population has low levels of circulating vitamin D. Additionally, observational studies have shown the association between vitamin D status and infections, chronic diseases such as cancer, diabetes, and cardiovascular disease. Recently it was observed that old patients with COVID-19 and vitamin D deficiency had enhanced severity of lung damage, longer stay at the hospital, and increased risk of death, suggesting that vitamin D plays an important role in the patient outcome from COVID-19. A high dose of vitamin D supplementation improved clinical recovery in a case-series report but in another study, no evident link between levels of vitamin D and risk of COVID-19 infection was found. Results also remain debatable for vitamin D supplements and improvement of immune response after vaccination, tuberculosis, pneumonia, and sepsis. It has been hypothesized that vitamin D could modulate the immune system and thus provide both efficacies in the immune response to pathogens/vaccinations and reduction of the inflammatory phenotype. This review will discuss vitamin D and homeostasis of the immune system; the literature-based clinical data on vitamin D and infections; and the possible link between vitamin D and immune response after vaccination.

Interest in the mechanisms of aging of the immune system has not faded over the past 100 years, and it is caused by the immune-mediated development of age-related pathology, including autoimmune organ damage, reduced vaccination efficiency, atherosclerosis, the development of cardiovascular pathology, etc. In contrast to many other organs and systems, the immune system aging begins at an early age and has more pronounced changes that lead to the development of secondary pathology, which significantly affects life expectancy. But an effective strategy to restore immune function has not been developed yet. During this time, the mechanisms of age-related dysfunction of organs and cells of both the adaptive and innate immune systems were studied in detail—thymus involution, a decrease in the potential of hematopoietic stem cells, impaired differentiation and functions of immunocompetent cells, as well as the ways of their interaction. Numerous potential therapeutic targets have been identified and various approaches have been used to implement such therapeutic interventions. The review is devoted to replacement therapy using transplantation of hematopoietic stem cells (HSCs) and young lymphoid cells and tissues, cellular and systemic factor exchange in heterochronic parabiosis, and some other widely used life extension approaches. It has been proven that cell therapy using young cells to rejuvenate the old immune system, unfortunately, often turns out to be ineffective because it does not eliminate the root cause of age-related changes. The phenomenon of inflamm-aging that develops with age can significantly affect both the aging of the organism in general and the functioning of immunocompetent cells in particular. Therefore, the most promising direction in the restoration of immune functions during aging is systemic approaches that have a complex effect on the organism as a whole and can slow down the aging process.

Periodontal tissue destruction can cause complaints for sufferers. Inflammatory conditions of the gingiva, bleeding gums, and even tooth loss are clinical features of the destruction of the periodontal tissues. Periodontitis is an inflammatory disease involving the periodontal tissues. The prevalence of periodontium destruction increases with aging. Changes in innate and adaptive immunity that occur in the elderly also play a role in the severity of periodontitis. “Inflammaging” is a chronic inflammatory state associated with old age in humans. Periodontitis contributes to inflammaging since periodontitis in the elderly is associated with increased markers of systemic inflammation. Age-related changes also affect neutrophil function, especially antimicrobial activity, so neutrophils may become more pathological. After infiltration into the tissue, neutrophils are equipped with several antimicrobial strategies to reduce the number of antigens. Phagocytosis is the ability of neutrophils to engulf and kill microbes, but neutrophil phagocytosis is weakened in the elderly. Age-related changes affecting neutrophils, macrophages, and T cells appear to promote pathogenic immune responses and contribute to the increased prevalence of periodontal disease in aging individuals. Proper regulation of the host immune response is critical in maintaining periodontal health. This paper aims to describe the aging process and its relation to periodontal conditions.

Human cytomegalovirus (HCMV), whose genome is around 235 kb, is a ubiquitous human herpesvirus that infects between 40% and 95% of the population. Though HCMV infection is commonly asymptomatic and leads to subtle clinical symptoms, it can promote robust immune responses and establish lifelong latency. In addition, in immunocompromised hosts, including individuals with acquired immunodeficiency syndrome (AIDS), transplant recipients, and developing fetuses it can lead to severe diseases. Immunosenescence, well-defined as the alterations in the immune system, is linked mainly to aging and has been recently gathering considerable attention. Senescence was characterized by an elevated inflammation and hence considered a powerful contributor to “inflammaging” that is measured mainly by tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) levels as well as latent viral infections, for instance, cytomegalovirus (CMV). Inflammaging resulted in a senescence-associated secretory phenotype (SASP). HCMV is markedly associated with accelerated aging of the immune system as well as several age-associated diseases that accumulate and subsequently deteriorate the immune responses, thus have been linked to mortality, declined vaccine efficacy, serious diseases, and tumors in the elderly. HCMV triggers or exacerbates immunosenescence; on the other hand, the weakened immune responses and inflammaging favor viral reactivation and highlight the role of HCMV in aging as well as viral-associated tumors. HCMV reactivation resulting in sequential lytic and latent viral cycles could contribute to HCMV genomic variability. Besides the oncomodulatory role and transforming capacities of HCMV, the immune-privileged tumor microenvironment has been considered the main element in tumor progression and aggressiveness. Therefore, the interplay between HCMV, immunosenescence, and cancer will aid in discovering new therapeutic approaches that target HCMV and act as immune response boosters mainly to fight cancers of poor prognosis, particularly in the elderly population.