Towards a Rigorous Definition of Cellular Senescence

The accumulation of lingering senescent cells is a significant cause of aging, disrupting tissue function and generating chronic inflammation throughout the body. Even while the first senolytic drugs capable of selectively destroying these cells already exist, and while a number of biotech companies are working on the production of rejuvenation therapies based on clearance of senescent cells, it is still the case that much remains to be settled when it comes to the biochemistry of these errant cells. More rigorous consensus definitions relating to the mechanisms, manifestations, and tissue specificity of senescence have yet to be pinned down. This process will proceed in parallel with the development of more effective therapies, as is often the case.

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers.

Over the last decade, improved experimental tools have significantly advanced our knowledge about causes and phenotypic consequences of senescent cells. However, specific markers and a consensus on the definition of what constitutes senescent cells are lacking. Further, although a link to organismal aging is clear, aging and senescence are not synonymous. Indeed, cells can undergo senescence, regardless of organismal age, due to myriad signals including those independent of telomere shortening. Consequently, senescent cells are detected at any life stage from embryogenesis, where they contribute to tissue development, to adulthood, where they prevent the propagation of damaged cells and contribute to tissue repair and tumor suppression. Thus, cellular senescence might be an example of evolutionary antagonistic pleiotropy or a cellular program with beneficial and detrimental effects.

Cellular senescence is a cell state triggered by stressful insults and certain physiological processes, characterized by a prolonged and generally irreversible cell-cycle arrest with secretory features, macromolecular damage, and altered metabolism. Senescent cells secrete a plethora of factors, including pro-inflammatory cytokines and chemokines, growth modulators, angiogenic factors, and matrix metalloproteinases (MMPs), collectively termed the senescent associated secretory phenotype (SASP) or senescence messaging secretome (SMS). The SASP constitutes a hallmark of senescent cells and mediates many of their patho-physiological effects. The SASP composition and strength varies substantially, depending on the duration of senescence, origin of the pro-senescence stimulus, and cell type.

The role of senescence in human disease is clear from cellular studies, while in vivo evidence is only now catching up. Evidence linking senescence to other common age-associated human diseases has recently emerged. These diseases include neurodegenerative disorders, glaucoma, cataract, atherosclerosis and cardiovascular disease, diabetes, osteoarthritis, pulmonary, and renal, and liver fibrosis. In most studies, senescence is assessed in ex vivo cultures or fresh samples by SA-β-gal staining or indirect markers in formalin-fixed tissues. Since SA-β-gal is not suitable for fixed tissues, analyzing senescence in human samples is challenging. Despite promising results from other individual markers, no marker is completely senescence specific. We recommend combining cytoplasmic (e.g., SA-β-gal, lipofuscin), nuclear (e.g., p16INK4A, p21WAF1/Cip1, Ki67) and SASP, context, and/or cell-type-specific markers.

Link: https://doi.org/10.1016/j.cell.2019.10.005

Comments

Has it been proven in humans that these cells are not simply correlated, but cause, aging?

Posted by: Eugene at November 10th, 2019 6:57 AM

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