This is a pre-print, not peer reviewed yet.
Abstract
Loss of proper T-cell functioning is a feature of aging that increases the risk of developing chronic diseases. In aged individuals, highly differentiated T cells arise with a reduced expression of CD28 and CD27 and an increased expression of KLRG-1 or CD57. These cells are often referred to as immunosenescent T cells but may still be highly active and contribute to autoimmunity. Another population of T cells known as exhausted T cells arises after chronic antigen stimulation and loses its effector functions, leading to a failure to combat malignancies and viral infections. A process called cellular senescence also increases during aging, and targeting this process has proven to be fruitful against a range of age-related pathologies in animal models. Cellular senescence occurs in cells that are irreparably damaged, limiting their proliferation and typically leading to chronic secretion of pro-inflammatory factors. To develop therapies against pathologies caused by defective T-cell function, it is important to understand the differences and similarities between immunosenescence and cellular senescence. Here, we review the hallmarks of cellular senescence versus senescent and exhausted T cells and provide considerations for the development of specific therapies against age-related diseases
1 INTRODUCTION
The incidence of age-related diseases such as Alzheimer’s Disease, diabetes, cardiovascular disease, and cancer rapidly rises. Impaired or maladapted immune responses are common in age-related diseases (Isobe et al., 2017). In addition, older individuals are more vulnerable to novel infections (Zheng et al., 2020). As the global population is aging, this poses a significant burden on healthcare systems worldwide. Therefore, several recent studies have investigated the aged immune system and tested different strategies to protect the elderly from age-related diseases and infections.
The cells in our body are constantly exposed to various stressors, including reactive oxygen species, toxins, DNA damage, and strong mitogenic signals induced by oncogene expression. When the damage to a cell cannot be repaired, it may undergo apoptosis or enter a state known as cellular senescence (Gorgoulis et al., 2019). This stable state of cell cycle arrest assures that the dysfunctional cell ceases proliferation. Senescence is an important mechanism in our body to prevent tumor development. In addition, temporary senescence plays a beneficial role in tissue remodeling during embryonic development, wound healing, the involution of the mammary glands after the cessation of breastfeeding, and the placenta after labor (Demaria et al., 2014; Sirinian et al., 2022).
Once a cell has entered a state of senescence, it may be cleared by the immune system (Xue et al., 2007). However, as the individual ages, the ability of the immune system to effectively eliminate senescent cells begins to decline. As we age, senescent cells accumulate and become a chronic feature within the body. Immune aging or immunosenescence affects both the innate and adaptive immune system. This process results in decreased responsiveness to vaccines and increased susceptibility to infections and cancer among the elderly (Fulop et al., 2017).
The aging process has a significant impact on the T cell compartment. The process of thymic involution, along with lifelong exposure to latent viruses, leads to a decrease in overall T-cell immunity and the emergence of T cells with reduced expression of CD28 and CD27, and increased expression of KLRG-1 or CD57, which are often referred to as senescent or immunosenescent T cells (Rodriguez et al., 2020). However, whether these T cells are truly senescent cells remains to be determined. Unfortunately, the term “senescent” is ambiguous when applied to T cells.
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