The state of the immune system is an important determinant of aging. With age, immune function both declines in effectiveness and becomes inflammatory. Chronic inflammation accelerates the progression of all of the common age-related diseases. It disrupts tissue maintenance and regeneration, to pick one of many examples. It is likely that a sizable component of variation in aging arises from the differences between individuals in the degree to which the immune system has become damaged and dysfunctional.
Some of this immune aging is a matter of the burden of exposure to more rather than fewer pathogens over a lifetime: persistent infections in particular, such as cytomegalovirus and other herpesviruses, appear to drive immune aging. Some immune aging stems from the atrophy of the thymus, the organ responsible for maturation of T cells. A lesser volume of active thymic tissue means fewer new T cells to take up an effective defense of the body. Some immune aging is due to failure of barriers in the gut, allowing gut bacteria to trigger inflammatory activity. Some immune aging arises from cellular senescence among immune cells, turning them into harmful centers of inflammatory signaling. All of these issues have potential solutions, but, as in all matters related to aging, far too little funding and attention are given to the relevant development programs.
Pro-inflammatory immune responses are our first line of defence against infectious non-self. Inflammation however, has a cost. During the life-history of a human, low-grade inflammation, develops gradually and contributes to the pathogenesis of a range of age-related diseases from leaky gut to neurodegeneration. Conversely, ageing through cell senescence, can influence immune function with the depletion of the pool of naïve T-cells ready to respond to infection making older individuals more vulnerable to viral disease and less responsive to vaccination regimes. This can in turn, influence human lifespan. In the apparent complexity of this dual relationship it is difficult to arrive at a mechanism of causality because cause and consequence are intimately linked.
Compromised intestinal barrier function in humans has been associated with conditions such as Crohn's disease. Changes in the permeability of the mouse gut, which results in "leaky gut" has consequences on health span. In this context, increased age-associated levels of Tumour Necrosis Factor (TNF) have a negative impact on gut permeability and impacts on lifespan while IL-10 knockout mice have (along with their immune defects) increased intestinal permeability and develop early colitis compromising health span and lifespan. In contrast, TNF-deficient mice are protected from age-associated inflammation.
There is now increasing evidence that inflammation regulates ageing. But which tissues contribute to this is less clear. Brain neuroinflammation represents a critical factor contributing to progression of neurodegeneration. NF-κΒ is the major regulator of inflammation and its sustained activation in forebrain neurons elicits a selective inflammatory response accompanied by decreased neuronal survival and impaired learning and memory. More recent experiments of transient NF-κΒ activation in astrocytes (a type of microglia) through a diverse array of inflammatory cues (infection or application of pro-inflammatory cytokines), resulted in non-cell autonomous neurodegeneration. The central position of microglia innate immunity in neurodegeneration and especially in the risk for late on-set Alzheimer's Disease (AD) is exemplified in human genome-wide association studies. Loss of TREM2 has been associated with increased risk of late on-set AD and increased TREM2 expression in mouse microglia had an anti-inflammatory rescuing effect with the downregulation of several pro-inflammatory markers. This ameliorated the neuropathological and behavioural deficits of AD mouse models.
T cells and B cells undergo immune senescence. Senescence is age-dependent and is the driving force for immune ageing. During ageing, both T and B cells will be depleted and the memory B cells, long-lived plasma cells and peripheral T-cells show defects. In addition, the provision by the thymus of naïve T-cells for the adaptation to new pathogens is limited. The mechanisms of these age-related defects are not fully elucidated but reduced autophagy, is a major driving force for immune senescence. In murine T cells, neutrophils and macrophages, autophagy is attenuated during ageing and autophagy-deficient cells display premature ageing traits.
Germ-free mice live almost 100% to 600 days in contrast to their conventionally-reared counterparts that reach this point with a 60% survival probability. In addition, germ free mice do not display age-associated inflammation while their macrophages retain their antimicrobial activity. This indicates that age-associated changes of the microbiota are a significant driver of lifespan where TNF-mediated inflammation acting as an effector of morbidity. Indeed, treatment of mice with anti-TNF antibodies reversed age-associated changes in the microbiota and ameliorated life expectancy. Therefore, reversing these age-related microbiota changes represents a potential strategy for reducing age-associated inflammation and the accompanying morbidity.