The accumulation of senescent cells with age is one of the root causes of aging. Senescent cells never amount to more than a few percent of all cells, even in late life, but they secrete a mix of extracellular vesicles and various proteins that is inflammatory and disruptive to tissue function. This is known as the senescence-associated secretory phenotype, or SASP. Since senescent cells inflect harm through signaling, it doesn't take many such cells to act as a contributing cause of age-related disease and organ dysfunction.
The research community is nowadays fully invested in the concept that senescent cells are a meaningful cause of aging. This is a comparatively recent development, despite the fact that the evidence was sizable and evident for several decades. It took a great deal of hard work, advocacy, and philanthropy in order to bring about this change; the medical research and development communities had essentially relinquished their responsibilities in the matter of aging. Now, however, there is a great deal of funding for research groups interested in the biochemistry of senescent cells.
While most clinical development is focused on selective destruction of senescent cells as a way to reverse their contribution to the aging process, and this seems the best path forward, there is nonetheless a sizable faction in the research community whose members are more interested in modulating the bad behavior of senescent cells. This largely means interfering the generation or consequences of the SASP in some way. One of the consequences of SASP signaling is that nearby cells are encouraged to become senescent themselves. In today's open access paper, the authors report on their investigation of the mechanisms involved in this behavior.
The establishment of cellular senescence is categorized by a stable cell-cycle arrest and the capacity to modify the microenvironment through a particular secretome called SASP (senescence-associated secretory phenotype). The activation of senescence is a response to different cellular stresses to prevent the propagation of damaged cells and has been shown to occur in vitro and in vivo. In fact, an enrichment in the number of senescent cells has been observed in vivo during both biological and pathological processes such as development, cancer, fibrosis, and wound healing.
The SASP controls its surroundings by reinforcing senescence in an autocrine (cell autonomous) and paracrine (non-cell autonomous) manner, by recruiting immune cells to eliminate senescent cells and by inducing a stem cell-like phenotype in damaged cells. The SASP provides the necessary balance to restore tissue homeostasis when it has been compromised. Paradoxically, the SASP can also contribute to the enhancement of tissue damage and the induction of inflammation and cancer proliferation. Overall, the mechanisms behind the pleiotropic activities of the SASP in different contexts are not well understood.
Most studies in vitro and in vivo have attributed the diverse functions of the SASP to individual protein components such as interleukin-6 (IL-6) or IL-8 to reinforce autocrine senescence or transforming growth factor β (TGF-β) as the main mediator of paracrine senescence or to a dynamic SASP with a switch between TGF-β and IL-6 as predominant individual components. However, it is still unclear how these diverse SASP components regulate senescence. In fact, inhibition of the SASP by blocking the mammalian target of rapamycin (mTOR) only partially prevents paracrine senescence, suggesting that alternative mechanisms may exist.
Exosomes are small extracellular vesicles (sEVs) (30-120 nm) of endocytic origin, whereas microvesicles are formed by the shedding of the plasma membrane. Exosomes and microvesicles are secreted by all cell types and found in most bodily fluids. Although some studies have found an increase in the number of EVs released during senescence, very little is known regarding the role that EVs play as SASP mediators in the senescent microenvironment.
Here, we show that both the soluble and sEV fractions of the SASP transmit paracrine senescence. The analysis of individual cells internalizing sEVs using a reporter system shows a positive correlation between the uptake of sEVs and paracrine senescence. sEV protein characterization by mass spectrometry (MS) followed by a functional small interfering RNA (siRNA) screen identify the interferon (IFN)-induced transmembrane protein 3 (IFITM3) within sEVs as partially responsible for transmitting senescence to normal cells. It is interesting that elderly human donors release more sEVs and that the sEVs found in plasma show higher protein levels of IFITM3 in 60% of the elderly donors. Although it may be tempting to speculate that IFITM3 within sEVs could be involved in aging, a larger cohort of young and elderly patients would be needed.
In conclusion, we show here that sEVs are responsible for mediating paracrine senescence and speculate that they could be involved in inducing bystander senescence during therapy-induced senescence or aging. In fact, when compared to soluble factors, sEVs have different biophysical and biochemical properties as they have a longer lifespan than do soluble factors and they are more resistant to protease degradation. The idea that blocking sEV secretion could be a potential therapeutic approach to alleviate senescence "spreading" during chemotherapy-induced senescence or in aging tissues presents itself as a very attractive tool for the future.