Senescent cells accumulate with age, but are never more than a tiny fraction of somatic cells in most tissues, even in very late life. Senescent cells nonetheless cause considerable harm via the signals that they produce, the senescence-associated secretory phenotype (SASP). These signals provoke chronic inflammation, harmful remodeling of tissue, and dysfunctional activity in nearby cells.
That comparatively few senescent cells can cause an outsized level of pathology simply by existing is why the strategy of selectively destroying senescent cells with senolytic therapies produces such impressive results in animal studies. Removing accumulated senescent cells turns back degenerative aging. A meaningful fraction of the inflammatory, disrupted state of aged tissue is actively maintained by the SASP generated by senescent cells.
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A number of features of senescence have been characterized, which could be used as proper biomarkers or potential therapeutic targets. Senescent cells generally display dramatically morphological changes, increased β-galactosidase activity, stable cell cycle arrest, persistent DNA damage response, metabolic reprogramming, and significant chromatin remodeling. The secretion of senescence-associated secretory phenotype (SASP) factors change the tissue microenvironment and affect even remote tissue via paracrine mechanisms, which is believed to contribute to organ degeneration with aging.
The phenotypic manifestations of SASP are heterogeneous and induced by different internal and external stimulus including telomere attrition, DNA damage, oncogenic activation, mitochondrial dysfunction, or epigenetic alterations. The SASP factors are mainly made of different types of soluble components including pro-inflammatory cytokines, growth factors, chemokines, and extracellular matrix-degrading proteins. This particular combination of signaling factors and the proteases that degrade extracellular matrix (ECM) to facilitate signal transduction has made SASP a powerful mechanism to modulate intercellular communication. The secretion of SASP factors is considered as a major detrimental aspect of senescence because it promotes chronic inflammation, induces fibrosis, and causes stem cell exhaustion.
However, it has also been shown to favor embryonic development or wound healing, suggesting whether beneficial or detrimental effects the SASP exerts depends on the physiological and pathological context. For example, a recent study has shown that transiently exposing the primary mouse keratinocytes to SASP factors increased cell stemness and regenerative capacity in vivo, while prolonged exposure caused secondary senescence and hindered regeneration. This suggests senescence has more complicated physiological roles than currently understood.
Senescence and its secretion phenotype SASP are the most fundamental player that could systematically change physiological functions at the intercellular level and reshape the tissue microenvironment toward aging. They directly change compositions of cell population by arresting the proliferation of progenitor cells or release pro-inflammatory factors to chronically elevate basal inflammation level causing systematic inflammaging. The effects of senescence and SASP are “erosive.” Once it starts, it has the potential to spread via the flowing cytokines to induce remote secondary senescence.
Elimination of senescent cells by senolytic drugs has been proven to be effective to counteract senescence in natural aging or age-related disease model. Recently, the first clinical trial of senolytic drug was conducted in human with idiopathic pulmonary fibrosis (IPF). Surprisingly, instead of rescuing lung functions, there was significant improvement in locomotor function such as walking distance or gait speed. Although it is a mystery why the drug failed to take effect in lungs where the most of senescent cells exist in IPF patients, it is still exciting to see the improvement in motor functions which proved senescence communicates at inter-tissue levels. In the future, increasing the specificities of senolytic drugs might help to better cure aging-related diseases.
Link: https://doi.org/10.3389/fphys.2021.702276
Source: Fight Aging!
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