A Review of Efforts to Target Senescent Cells in Order to Treat Age-Related Disease

This review paper looks at the present range of strategies adopted by the research and development communities in their efforts to target senescent cells. The accumulation of senescent cells is a contributing cause of aging; many animal studies have demonstrated reversal of aspects of age-related disease via clearance of senescent cells, particularly for those conditions in which chronic inflammation plays an important role. Senescent cells are comparatively few in number even in later life, but cause harm via secreted signals, a potent mix of proteins and vesicles known as the senescence-associated secretory phenotype (SASP). The SASP drives inflammation, changes the behavior of nearby cells for the worse, and destructively remodels surrounding tissue.

As there is ample evidence placing senescent cells as one of the causes of age-related dysfunctions, it has been considered to be one of the hallmarks of aging. It was recently demonstrated that elimination of senescent cells by genetic or pharmacological approaches delays the onset of aging-related diseases, such as cancer, neurodegenerative disorders, or cardiovascular diseases, among others, showing that the chronic presence of these cells is not essential. Conversely, local injections of senescent cells drive aging-related diseases. This data, together with that obtained from tissues of patients with different diseases and ages, has established causality of senescent cells in some aging-related pathologies.

One option to eliminate the negative effects of chronic senescent cells is to kill them specifically, using compounds called senolytics, which target pathways activated in senescent cells. The list of these senolytic compounds is extensive and continuously growing Senolytics target key proteins mainly involved in apoptosis, such as Bcl-2, Bcl-XL, p21, PI3K, AKT, FOXO4, and p53. Although senolytics are supposed to be specific for senescent cells, there are always unwanted damage/side effects since the administration is not directed. In this regard, a new strategy has been recently described to specifically target senescent cells in mice, using nanocapsules containing toxins (or senolytics). The outer layer of these nanocapsules are composed of substrates for enzymes that are overexpressed in senescent cells. In this way, the toxin (senolytic) will only be released inside senescent cells, killing them.

Another strategy to inhibit the functions of senescent cells is through the specific silencing of SASP, the complex mixture of soluble factors such as cytokines, chemokines, growth factors, proteases, and angiogenic factors that mediates the paracrine and autocrine functions of senescent cells. Senomorphics inhibit SASP functions by targeting pathways such as p38 mitogen-activated protein kinase (MAPK), NF-κB, IL-1α, mTOR, and PI3K/AKT, which act at the level of transcription, translation, or mRNA stabilization. Alternatively, inhibition may be achieved by specific antibodies against individual SASP factors (protein function inhibition), as is the case for IL-1α, IL-8, and IL-6. One doubt about this strategy is how SASP-silenced/attenuated senescent cells would be cleared. Given that some SASP factors are involved in the recruitment of immune cells, SASP inhibition could make senescent cells effectively "invisible" to the immune system, therefore remaining chronically within the tissue.

A third strategy to target senescent cells is to strengthen the immune system for efficient recognition and elimination of these cells, a process termed immunosurveillance. The role of the immune system in the elimination of senescent cells is fundamental, and a decline in immune function is associated with an increase in the number of senescent cells and finally, disease. In this regard, there are two strategies: i) improving the specific anti-senescent cell functions; and ii) general enhancement of immune functions (to avoid senescence of immune cells involved in recognition of senescent cells). Anti-senescent cell functions have been described in NK cells, macrophages, and CD4+ T cells. Since these functions take place through membrane receptors, one option is to increase the binding affinity of the involved receptors. In this sense, the use of chimeric antigen receptor (CAR) T cells to target specific senescent-related molecules would be an attractive approach.

Link: https://doi.org/10.18632/aging.102557

Comments

Quite interesting, when will the nanocapsules be available? Also, in regard to " third strategy to target senescent cells is to strengthen the immune system for efficient recognition and elimination of these cells" - Woud it help to rev up the immune system with 800-1200 mg of tagamet prior to taking fisetin or other senolytic therapy?

Posted by: AUGUST33 at December 13th, 2019 11:14 AM

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