Stochastic damage to cellular macromolecules and organelles is thought to be a driving force behind aging and associated degenerative changes. However, stress response pathways activated by this damage may also contribute to aging. The IKK/NF-κB signaling pathway has been proposed to be one of the key mediators of aging. It is activated by genotoxic, oxidative, and inflammatory stresses and regulates expression of cytokines, growth factors, and genes that regulate apoptosis, cell cycle progression, cell senescence, and inflammation. Transcriptional activity of NF-κB is increased in a variety of tissues with aging and is associated with numerous age-related degenerative diseases including Alzheimer’s, diabetes and osteoporosis. In mouse models, inhibition of NF-κB leads to delayed onset of age-related symptoms and pathologies. In addition, NF-κB activation is linked with many of the known lifespan regulators including insulin/IGF-1, FOXO, SIRT, mTOR, and DNA damage. Thus NF-κB represents a possible therapeutic target for extending mammalian healthspan.

Frailty is an important geriatric syndrome that is characterized by multisystem dysregulation, leading to decreased physiological reserve and increased vulnerability for adverse health outcomes. A large number of studies have shown a heightened inflammatory state marked by elevated levels of inflammatory molecules, such as IL-6 and C-reactive protein (CRP), and increased counts of white blood cell (WBC) and WBC subpopulations in frail older adults. It has been postulated that this heightened inflammatory state, or chronic inflammation, may play an important role in the pathogenesis of frailty, directly or through its detrimental influence to other physiologic systems. Inflammatory and immune activation mediated by monocytes and macrophages demonstrated by upregulated expression of specific stress responsive inflammatory pathway genes and elevated neopterin levels may contribute, at least in part, to this chronically heightened inflammatory state in frailty. Decrease in lipopolysaccharide (LPS)-induced proliferation of the peripheral blood mononuclear cells (PBMCs), one of the functional readouts of the innate immune system, has also been observed in frail older adults. In the adaptive immune system, significant frailty-associated alterations have been identified in the T-cell compartment including expansion of CD8⁺ and CCR5⁺ T cells and loss of CD28 expression, above and beyond age-related senescent remodeling. Moreover, frailty is associated with impaired antibody responses to pneumococcal and influenza immunization and poor clinical protection against influenza infection in community-dwelling older adults. Taken together, these findings demonstrate significant inflammatory and immune dysregulation in frail older adults and highlight the need for strategies to improve the immune function for this vulnerable elderly population.

Aging is associated with the chronic, low grade, Th-1 type inflammation. The key Th-1 type, pro-inflammatory cytokine, interferon-gamma (IFNG), transcriptionally induces the rate-limiting enzyme of tryptophan (TRY) – kynurenine (KYN) pathway, indoleamine 2,3- dioxygenase (IDO). Activation of IDO shunts TRY metabolism from production of serotonin (substrate of antidepressant effect) and its derivatives: N-acetylserotonin (an agonist to the receptors of brain derived neurotropic factor), and melatonin (regulator of sleep and other circadian rhythms), towards production of KYN and its derivatives (anxiogenic, neurotoxic and pro-oxidant factors). Some of kynurenines up-regulate nitric oxide synthase (NOS). Concurrently with activation of IDO, IFNG induces guanosine triphosphate cyclohydrolase I (GTPCH), the rate limiting enzyme of GTP conversion into BH2 (and increases formation of a stable derivative of BH2, neopterin, at the expense of production of BH4, the mandatory co-factor of NOS). Combination of increased NOS activity (by kynurenines) with decreased formation of BH4 leads to the uncoupling of NOS with consequent shift of arginine metabolism from biosynthesis of NO to formation of superoxide anion and other free radicals, and exacerbation of depression, anxiety and cognitive impairment caused by kynurenines. Polymorphism of IFNG (+874) T/A gene, that encodes production of IFNG protein, impacts the IDO and GTPCH activity that might be assessed in humans by KYN/TRY ratio and neopterin concentrations in biological fluids (e.g., blood, urine and spinal fluid). The hypothesis of IFNG inducible IDO/GTPCH inflammation cascade helps to understand the increased association between aging, inflammation and aging-associated psychiatric and medical (insulin resistance, obesity) disorders. Evaluation of markers of IFNG-inducible inflammation cascade might be used to assess the severity of corresponding behavioral and cognitive changes and the efficacy of pharmacological interventions (e.g., IDO inhibitors).

Advances in modern medicine have led to an increase in the median life span and an expansion of the world’s population over the age of 65. With increasing numbers of the population surviving to the extreme of age, those at risk for the development of pneumonia will approach 2 billion by the year 2050. Numerous age-related changes in the lung likely contribute to the enhanced occurrence of pneumonia in the elderly. Inflammation in the elderly has been shown to increase risk prior to infection; age-associated inflammation enhances bacterial ligand expression in the lungs which increases the ability of bacteria to attach and invade host cells. Conversely, the elaboration of the acute inflammatory response during early infection has been found to decrease with age resulting in a delayed immune response and diminished bacterial killing. Finally, the resolution of the inflammatory response during the convalescent stage back to “baseline” is often prolonged in the elderly and associated with negative outcomes, such as adverse cardiac events. The focus of this review will be to discuss our current understanding of the potential mechanisms by which dysregulated inflammation (both prior to and following an infectious insult) enhances susceptibility to and severity of community acquired pneumonia (CAP) in the elderly with an emphasis on pneumococcal pneumonia, the leading cause of CAP.

Older age has long been associated with altered inflammation and hemostasis regulation. Emerging evidence suggests that age-related differences in inflammation and hemostasis abnormalities may play a role in the development of and long-term outcomes after critical illness. A better understanding of underlying mechanisms may provide new possibilities for therapeutic interventions. In this review, we will examine how age-related differences in inflammatory and coagulation responses are affected through the continuum of healthy state, before infection occurs, to severe sepsis and recovery.

The deterioration of immune function with advancing age is associated with an increased incidence of cancer. Most of the studies to evaluate the effect of immunotherapy on cancer have been conducted in the young without considering the effect of age-associated changes in immune function. Studies from my laboratory and others groups indicate that immunotherapeutic interventions could be effective in young animals, but that the same therapies are not as effective in old animals. The present review summarizes some defects found in the old immune system affecting the activation of antitumor immune responses, the strategies used to activate a more robust antitumor immune response in the old and the description of a preclinical tumor model indicating possible strategies for optimization of immunotherapeutic interventions in the old.

Immune aging is associated with loss of critical immune functions, such as host protection from infection and malignancy. Unexpectedly, immunosenescence also renders the host susceptible to inflammation, which may translate into tissue-damaging disease as the senescent immune system loses its ability to maximize inflammatory protection while minimizing inflammatory injury. On the other hand, chronic inflammation associated with immune-mediated disease represents a profound stress factor for the immune system, affecting cellular turn-over, replication and exhaustion. Immune cell longevity is tightly connected to the functional integrity of telomeres which are regulated by cell multiplication, exposure to oxidative stress and DNA repair mechanisms. Lymphocytes are amongst the few cell types that can actively elongate telomeres through the action of telomerase. In patients with the autoimmune disease rheumatoid arthritis (RA), telomerase deficiency is associated with prematurity of immune aging. Patients with RA have other defects in DNA repair mechanisms, including the kinase Ataxia telangiectasia mutated (ATM), critically involved in the repair of DNA double strand breaks. ATM deficiency in RA shortens lymphocyte survival. Dynamics of telomeric length and structure are beginning to be understood and have distinct patterns in different autoimmune diseases, suggesting a multitude of molecular mechanisms defining the interface between chronic immune stimulation and progressive aging of the immune system.

The immune system declines with aging, leading to an increased susceptibility to infections and higher incidence and progression of autoimmune phenomena and neoplasia. Down syndrome prematurely shows clinical manifestations that are normally seen with aging. This review provides a concise overview of abnormalities in the adaptive immune system of Down syndrome in comparison to normal and precocious (Progeria syndromes) aging. Clinical signs and immunological changes are reviewed. We challenge the hypothesis that the immunological abnormalities in Down syndrome should be interpreted as precocious immunosenescence.