Arguing for a Central Role of Cellular Senescence in the Age-Related Susceptibility to Inflammatory Conditions

Inflammation is a necessary part of the immune response to injury and infection, required in order to defend and rebuild. Normally, inflammation is a cycle of signaling that changes cell behaviors, response followed by resolution. When resolution fails, serious consequences can result. Conditions such as sepsis and severe COVID-19 cases are examples of a runaway inflammatory response leading to a high mortality. Both of these examples are age-related, in the sense that old people are far more susceptible to undergoing such a breakdown of the normal inflammatory feedback loops. The age-related dysfunction of the immune system predisposes it to overactivation and inflammation, just as it also makes the immune response less effective.

Senescent cells accumulate with age. These cells are constantly created and cleared in the body, and when present for only a short time play an important role in cancer suppression and wound healing. With age, however, the pace of creation accelerates and pace of clearance by the immune system slows. A constant presence of senescent cells allows their inflammatory, pro-growth senescence-associated secretory phenotype (SASP) to grow to pathological levels, encouraging a rising level of chronic inflammation throughout the body. It is hypothesized that this is an important cause of age-related susceptibility to runaway inflammation in response to circumstances that the regulatory mechanisms of young individual would successfully cope with.

Senescence-associated hyper-activation to inflammatory stimuli in vitro

Advancing age is associated with a multitude of physical and physiological deteriorations that leave the elderly susceptible to a wide variety of pathological conditions. Consequently, there is a steep decline in the health-related quality of life for the elderly. Amongst a wide variety of conditions, increased susceptibility to severe infections (such as COVID-19) and inflammatory conditions (such as sepsis) is one such age-related phenomenon. Despite representing under 25% of the population, people older than 60 account for more than 75% of sepsis related death. With respect to COVID-19, people over 60 are three times more likely to die from a severe infection than people under 60. The severity of disease progression in these population upon infection is partially attributed to the higher prevalence of severe cytokine storm in the elderly. Though there are many theories as to what makes the elderly susceptible to severe cytokine storm, there is no commonly accepted explanation to this phenomenon.

Cellular senescence is a phenomenon by virtue of which stressed or damaged cells undergo a permanent cell cycle arrest. In healthy individuals, senescent cells (SnCs) are cleared rapidly by the immune system. This clearance mechanism has been shown to become impaired with advancing age, leading to the accumulation of SnCs. In turn, the accumulation of SnCs has been implicated in many age-related pathologies and diseases. The detrimental effects of SnCs are partly a consequence of their expression of the senescence-associated secretory phenotype (SASP). The SASP includes an extensive list of factors such as inflammatory cytokines, chemokines, and matrix metalloproteases (MMPs), which are detrimental to the normal functioning of neighboring cells.

Hence, we hypothesized that SnCs contribute to the increased severity of infectious diseases and infection-mediated cytokine storm in the elderly through the expression of the SASP. To test this hypothesis, we examined whether SnCs exhibit hyper-activation to LPS, IL1β, and TNFα stimulation. Our results show that SnCs indeed have a greater proclivity to become hyper-activated in response to inflammatory insults, resulting in the increased production of a variety of inflammatory cytokines and chemokines when compared to their non-senescent counterparts, which we term senescence-associated hyper-activation. Senescence-associated hyper-activation may be attributable to a higher basal activation of the p38 mitogen activated protein kinase (p38) and NF-κB pathways. These findings lay a foundation to elucidate the important role of SnCs in the age-related increased susceptibility to severe infections and inflammatory conditions.

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