Cellular senescence is one of the root causes of aging. Nonetheless, the study of cellular senescence used to be a comparative backwater in aging research, and as a topic it was mostly of interest to cancer researchers seeking ways to better shut down the replication of cancerous cells. But there is nothing quite like having a company raise $300 million in venture funding for rejuvenation therapies based on manipulation and destruction of senescent cells to bring a little excitement to this part of fundamental aging research. Who knows how many useful, exploitable mechanisms are yet to be found in senescent cells and the signals they generate? Each one is a potential lottery ticket for the discovering institution and research group.

This was in fact always the case, and for decades a compelling set of evidence has strongly suggested that the accumulation of senescent cells is a significant contribution to aging. Yet next to no-one was funding or working on it seriously until the high-profile proof of concept study in mice reported in 2011, in which senescent cells were eliminated and health and life span improved as a consequence. After that point, the avalanche started, leading to today's crop of first generation senolytic therapies capable of selectively destroying a fraction of the senescent cells present in older individuals.

Today I thought I'd point out a couple of examples of the sort of paper that results from an influx of funding and interest to the study of the fundamental biochemistry of senescent cells. The research community is mining for gold. The first explores the harmful signals secreted by senescent cells, the major way in which they cause tissue dysfunction in aging and age-related disease. A faction within the research community is more comfortable interfering in these signals rather than destroying senescent cells, despite it likely being a far worse and more challenging approach to therapy. The second paper is one of many in which researchers explore the role of mitochondrial activity in senescence, in search of approaches that might modulate the activity in beneficial ways. Both papers are quite different in focus, but they emerge from the same newfound interest in senescence as a cause of aging.

Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype

Senescent cells lose their cell type specific functionality and replicative potential required for tissue regeneration and acquire a senescence-associated secretory phenotype (SASP). The SASP is characterized by the secretion of growth factors, pro-inflammatory cytokines and chemokines, as well as extracellular matrix (ECM) remodeling enzymes. These SASP factors are considered to over-proportionally exert negative effects on tissue homeostasis and regeneration in vivo if chronically present by acting in a paracrine manner on the neighboring cells and ECM. Attenuation of the negative effects of the SASP have been shown to restore the formation of functional human skin equivalents and has been suggested as a putative target in preventing age-associated diseases and frailty. Recently, extracellular vesicles (EVs) and their cargo have been reported to act in a similar manner as hormones or cytokines during intercellular communication. They are secreted by many, if not all cells, and by encapsulation of their cargo, they transport proteins, mRNAs, lipids, and non-coding RNAs, specifically miRNAs, over short or long distances. Thus, although many protein based SASP factors have been identified, miRNAs and EVs are under suspicion to be part of the SASP. However, a systematic catalogue of SASP-miRNAs has not yet been established and their selective secretion during senescence has not been studied so far. Here, we confirm that EVs and their miRNA cargo are indeed part of the SASP (EV-SASP) and identified a set of selectively retained and secreted miRNAs after the onset of senescence. In addition, senescent cell derived EVs might contribute to an anti-apoptotic environment in tissues where senescent cells have accumulated.

Mitochondrial peptides modulate mitochondrial function during cellular senescence