The effects of Inflammation

Aging involves changes in biological, physiological,immunological, environmental, psychological, behavioral, and social processes.Key hallmarks include genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis. Aging is nonlinear and highly context-dependent, with each individual's unique genetics and life history affecting their "exposome." Immunologically, the combination of type,intensity, and temporal sequence of antigens determines an individual's immunobiography,influencing antigenic molecules' strength or tolerance.

Aging is linked to functional changes in the immune system,known as immunosenescence, which can have negative consequences for the host.Cellular senescence, which involves irreversible exit from the cell cycle dueto damage or stress, is also associated with aging. Senescent cells acquire aninflammatory senescence-associated secretory phenotype (SASP), and thearchitecture of lymphoid organs and structures also exhibits age-associatedchanges. Inflammaging, a low-grade chronic process, is mainly related tosenescent cells and their associated secretory phenotype, contributing toorganismal aging.

The concept of immunosenescence has evolved over the pasttwo decades, with the initial interpretation of differences between younger andolder adults in immune function being detrimental. However, recent discoveriessuggest that not all changes in the immune system considered detrimental areactually harmful. Age induces a decrease in immune functions but may also leadto increased function in certain aspects, which can be viewed as adaptive. Anupdated and more comprehensive concept of immunosenescence is proposed as ahighly dynamic and multifactorial process, consisting of several changes inimmune responses. The most frequently described phenotypic differences betweenelderly and young individuals are the decrease in naïve T cell populations andthe increase in memory subpopulations, which are mostly adaptive changes ratherthan necessarily maladaptive. The age-dependent decline in naïve T cells andthe accumulation of memory T cell clones leads to a reduction in the diversityof the T cell repertoire in elderly individuals, potentially resulting indecreased capability to combat new pathogens and recall responses forpreviously encountered pathogens.

The complex changes in acquired immunity are likely due toepigenetic and metabolic modifications affecting immune cells. In youngerindividuals, hematopoietic stem cells (HSCs) produce a balanced output ofmyeloid and lymphoid progenitor cells. As individuals age, the preference foraged HSCs to differentiate into common myeloid progenitor cells leads to areduction in common lymphoid progenitor cell frequencies. This skewing ofimmune cell output from the bone marrow remains unclear. Chronic antigenic stimulation,such as persistent infections or altered tissues and molecules, drives theperipheral T cell compartment into a state different in older individuals,possibly representing exhaustion. Comparative studies are emerging on otherpopulations, such as Chinese and Pakistanis.

Immunosenescence is a process characterized by changes in Bcells, which significantly impact antibody production. In older adults, thenumber of circulating B cells decreases, leading to a decrease in IgD +CD27-naïve cells and an increase in IgD-CD27-double negative late memory Bcells. Advanced age also leads to specificity repertoire changes, modifiedperipheral B cell dynamics, and weakened humoral responses. Human obese adiposetissue contributes to systemic and B cell intrinsic inflammation, leading toincreased secretion of autoantibodies.

The debate around the reinterpretation of immunosenescence is influenced by theincreasing number of centenarians and semi-supercentenarians worldwide, mainlyin the blue zones. The most often cited vaccine failure in older adults isseasonal influenza, but this may not always be due to a decline in T-cellresponses. Future vaccines should include changes in composition, adjuvants,doses, and more mechanistic interventions. Centenarians are consideredsuccessful aging models due to their immune response maintaining adequatefunctionality and controlling inflammaging.

Immunosenescence in older adultsinvolves changes in B cells, impacting antibody production. The number ofcirculating B cells decreases, leading to a decrease in IgD + CD27-naïve cellsand an increase in IgD-CD27-double negative late memory B cells. Advanced agealso leads to specificity repertoire changes, modified peripheral B celldynamics, and weakened humoral responses.

Aging is a significant risk factor for age-related diseasesand geriatric syndromes, but it's not uniform in every individual.Immunosenescence is characterized by a decrease in naïve T and B cells, anincrease in memory cells, and inflammaging, but their clinical relevance isoften unclear.

Inflammaging

Inflammaging refers to the low-gradechronic inflammatory status in older individuals, which is linked to areduction in efficient responses to new and previously encountered antigens andan increase in proinflammatory markers. This is associated with various age-relateddiseases such as atherosclerosis, cardiovascular diseases, type 2 diabetes,metabolic syndrome, osteoporosis, cognitive decline, neurodegenerativediseases, and frailty. Inflammaging and immunosenescence are mutuallyintertwined, with inflammaging-producing factors inducing immunosenescence andimmunosenescence-producing factors contributing to inflammaging. The process isdriven by cell senescence, imbalanced microbiome composition, innate immunememory, and metabolic epigenetic changes induced by the mitochondria. Invasivemicrobes may induce proinflammatory mediators and enhance inflammation. Thetrained innate immunity concept suggests that the innate immune system is in achronic activation state, potentially benefiting the next response.

Cellsenescence and chronic inflammation

Cellular senescenceis a cell fate characterized by irreversible cell-cycle arrest, secretoryfeatures, macromolecular damage, and altered metabolism. It is implicated invarious physiological processes in addition to aging and is associated with awide spectrum of age-related diseases. Cellular senescence is not a synonym foraging and is not exclusive to advanced age or pathologic processes. A cell caninitiate the senescence program regardless of organismal age, contributing totissue development and later playing a role in tissue repair and tumorsuppression.

Senescence is primarily associated with detrimental effects, which can betriggered by a number of stress signals to the cell, including DNA damage,telomere shortening or dysfunction, oncogene activation or loss of tumorsuppressor functions, mitochondrial dysfunction, nutrient deprivation, hypoxia,and epigenetic changes. The main cause of senescent stress is DNA damage, whichactivates the DNA damage response (DDR) and the canonical p53–p21 pathway, andin consequence leads to cell-cycle arrest.

The senescent-associated mitochondrial dysfunction (SAMD) constitutes ahallmark of senescence and mediates many of its patho-physiological effects.Senescent cells secrete bioactive molecules, especially pro-inflammatorycytokines and chemokines, contributing to systemic sterile chronic inflammationassociated with age-related diseases, frailty, and mortality in the elderly.However, the SASP includes more than pro-inflammatory factors, as ROS, growthfactors, matrix-remodeling factors, (non-coding) RNAs, as well as otherpeptides and proteins. The composition and intensity of SASP varies dependingon the pro-senescence stimulus, the duration of senescence, and cell type andmicroenvironment.

There is a close association between chronic inflammation and cell senescence.The SASP reinforces and spreads senescence in an autocrine and a paracrinemanner, leading to a positive feedback loop in which senescence causes chronicinflammation and inflammation causes senescence.

Senescent cells accumulate with age in multiple tissues and may causefunctional decline. In the immune system, senescence affects both innate andadaptive immunity, in particular follicular helper T cell and natural killercell function. A mouse model with a selective deletion of a DNA damage repairprotein in hematopoietic cells was generated to induce senescence in the immunesystem only. Remarkably, non-lymphoid organs from these mice also exhibitedincreases in senescence markers, suggesting that a senescent immune system hasa causal role in driving systemic aging.

Possible therapeutic strategies include targeting the aging process itself,promoting physical exercise and healthy nutrition, and dietary restrictionwithout malnutrition. Dietary restriction without malnutrition is the goldstandard for delaying aging and extending life and health in various species.Studies have demonstrated that genetic and epigenetic background determines theresponse to dietary interventions, including dietary restriction in mice.

Immune function is impaired with aging, leading to more severe infections andincreased mortality. Recent studies demonstrated that reducing the senescentcell burden and the inflammatory SASP by treatment with senolytic andsenomorphic compounds improves the immune response and reduces mortality.Clinical trials have been conducted to test the effect of senolytics andsenomorphics.

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Chronic inflammation, which accompanies the aging process, differs inintensity, duration, and possibly in the composition of cytokines involved fromthe acute inflammatory response originating from infection or tissue injury.Effective inflammation is fundamental for tissue repair and clearance ofpathogens, but the nonresolved persistent inflammatory state in aging can beunderstood as a generally maladaptive response, occurring at a stage of lifenot subjected to selection during evolution.

A major stimulus continuously activating inflammatory signaling in aging isthe presence of damaged organelles and macromolecules that accumulate in oldorganisms. The self-debris and self-molecules that result from unhealthy ordead cells are produced at a higher rate in aged tissues, while the mechanismsresponsible for the disposal of harmful products of cellular damageprogressively decline. Many well-described strategies to delay aging andimprove health and lifespan, including caloric restriction, are interventionsthat can potentially reduce inflammation by activating mechanisms of cellulardamage disposal.

Another important source of inflammation in aging is the accumulation ofsenescent cells and their associated pro-inflammatory secretome. In this case,the removal of senescent cells, achieved through the use of senolytics or inmouse models where the selective elimination of senescent cells can bechemically induced, displays a reversal or improvement of key aspects of agingphenotypes. Recent work in short-lived African turquoise killifish indicatesthat microbiome transplantation from young to middle-aged killifish canincrease lifespan, pointing to microbiome composition as an aspect of healththat can be modulated to impact the aging process.

Aging research has also relied on the analysis animal models of progeria,where accelerated aging is observed due to specific genetic alterations thatphenocopy accelerated aging, activating several of the mechanisms describedabove. Importantly, interventions that reduce inflammation delay the onset ofage-associated features in progeroid mouse models, extending their longevity.From these observations, it becomes apparent that targeting inflammation couldbe envisioned as an intervention to allay age-related tissue dysfunction alsoduring physiological aging, an idea that is already beginning to be tested.

To refine our knowledge on the mechanisms linking inflammation andage-related tissue dysfunction, it is critical to develop reliable experimentalmodels that allow for the isolation of the inflammatory component of aging andthe evaluation of its independent contribution to other age-relatedalterations. These models would also be valuable tools to test the idea thatimmune modulatory interventions can indeed be applied to delay age-relatedtissue alterations and improve health span.

Although the etiology of age-related inflammation remains to be fullyelucidated, some recent tools are starting to be used to understand and mimicthe state of 'inflammaging' and evaluate its consequences. Researchers haveused a mouse model of increased NFjB signaling, a key signaling pathway drivingSASP-related pro-inflammatory cytokines, and a pro-inflammatory mediatorover-activated during normal aging, and in premature aging models. Analternative model of chronic inflammation relies on the loss of function (LOF)of the anti-inflammatory cytokine, interleukin 10 (IL-10), which results in alow grade proinflammatory state accompanied by signs of accelerated frailty atmiddle age.