Senescent cells are created constantly throughout life, but are rapidly removed by the immune system. Only in later life does the efficiency of immune clearance falter to allow senescent cells to accumulate. Lingering senescent cells cause harm in proportion to their numbers, secreting inflammatory signals that disrupt tissue structure and function. Numerous approaches to the selective clearance of senescent cells exist, and numerous companies are developing senolytic therapies that should improve health in later life, turning back aspects of aging by removing the senescent cells that are actively maintaining a degraded state of tissue function.
Instead of clearing senescent cells via present methods that attack features of senescent cell biochemistry to force apoptosis, is it possible to address the age-related changes that cause slowed immune clearance? On the one hand there are many avenues of research and development that might restore some lost function in the aged immune system, and it remains to be seen as to how they will affect surveillance of senescent cells. On the other hand, it appears that senescent cells in older individuals are different from those in younger individuals in ways that hamper the immune system. In today's open access paper, researchers find that senescent cells expressing GD3 at their cell surface can evade the attention of natural killer cells of the innate immune system. Sabotaging this mechanism would aid in immune clearance of senescent cells in aged individuals.
Advancing age goes hand in hand with the increased susceptibility to develop diseases that lead to functional decline, loss of autonomy, and healthcare system saturation. Mechanistically, the accumulation of senescent cells (SnCs) in tissues emerges as a key driver of aging and age-associated diseases. Thus, according to the geroscience hypothesis, considerable efforts are being made to find senotherapeutic strategies that allow the elimination or modification of SnCs to prevent and simultaneously treat many age-related diseases. Different senolytic compounds target the SnC intrinsic property to resist apoptosis due to Bcl-2 family protein overexpression.
Despite the existence of immune pathways to eliminate them, some SnCs can be tolerated in tissues for decades, and how they can be tolerated by the immune system remains an open question. The mechanisms by which these SnCs evade T cell surveillance can depend on immune checkpoints such as PD-L1. However, how SnC cells can evade from innate immunity, such as natural killer (NK) cell killing, is still elusive. In the present study, we discovered that SnCs can gain an immune privilege when they express at their cell surface a high level of the ganglioside GD3, leading to the escape from natural killer (NK) cell killing. This is the case for a large panel of SnC types, which upregulate the ST8SIA1 gene encoding the enzyme synthesizing GD3. In contrast, oncogene-induced SnCs do not trigger ST8SIA1 expression, enabling their elimination by NK cells.
Moreover, we demonstrate that anti-GD3 immunotherapy in mice prevents the development of bleomycin-induced lung fibrosis and attenuates different types of age-related disorders: lung and liver fibrosis and osteoporosis. These findings reveal GD3 as a senescence immune checkpoint and as a promising target for anti-senescence therapy.
View the full article at FightAging
