TLR4 is one of a number of cell surface receptors that mediate innate immune cell reactions to molecules indicative of damage in the body. Some fraction of the chronic inflammation of aging is caused by increases in damage-associated molecular patterns that trigger receptors of this nature, and consequent maladaptive reactions on the part of the innate immune system. Does it help to block this trigger? In mice, yes. Knockout of TLR4 leads to mice that have improved insulin metabolism and cardiovascular health in old age. TLR4 might be a good example of antagonistic pleiotropy. Natural selection has produced mice equipped with a more aggressive innate immune response, helpful in youth, at the cost of a more rapid deterioration in later life.
A growing amount of evidence suggests that inflammation plays a critical role in the physiological aging process. Many studies have shown that the activated chronic inflammatory response is involved in aging-related diseases. Aging-related inflammation is characterized by increased levels of IL-6, IL-1β, TNF-α, and type I interferon. This chronic activation of the innate immune system in the absence of infection during the aging process is called inflammaging. The activated innate immune system in aging causes insulin resistance and oxidative processes, making the cardiovascular system more vulnerable to stress, thereby increasing the risk of cardiovascular diseases. Moreover, some studies have shown that inhibiting inflammation could reduce the occurrence of cardiovascular diseases in aging, suggesting the important role of inflammation in aging-induced cardiovascular injury.
The mechanism responsible for inflammaging is still far from clear. Metabolic disorders, mitochondrial dysfunction, DNA damage, and autophagy deficiency are all involved in inflammaging. The damaged DNA or self-derived molecules released from damaged cells are called damage-associated pattern molecules (DAMPs). Usually, DAMPs are transferred into lysosomes and then degraded. The accumulation of excessive DAMPs will lead to inflammation. TLR4 is an innate immune receptor that specializes in sensing DAMPs. When sensing DAMPs, TLR4 triggers intracellular signaling pathways which subsequently activate downstream inflammatory responses, leading to the release of inflammatory factors.
The effects of TLR4 on the cardiovascular system of aged mice were investigated in TLR4-/- mice. In wild-type mice, TLR4 expression increased in the hearts and aortas of mice in an age-dependent manner. Loss of TLR4 increased insulin sensitivity in aged mice. Moreover, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. Importantly, the increases in serum inflammatory cytokines and oxidative stress in the heart and aorta were also inhibited by TLR4 deficiency. The reduced inflammatory responses and oxidative stress may be the reason for the protective effects of TLR4 deficiency during aging. Our study indicates that targeting TLR4 is a potential therapeutic strategy for preventing aging-related cardiovascular disease.