Senescent cells accumulate with age throughout the body. Cellular senescence occurs most often at the end of a cell’s replicative life span, but can also be provoked by damage, a toxic environment, or the signaling of other nearby senescent cells. Senescent cells are metabolically active and secrete a potent mix of pro-inflammatory, pro-growth signals. This state has a number of useful functions, such as coordination of wound healing and elimination of potentially cancerous cells. In youth senescent cells are promptly destroyed by the immune system or programmed cell death processes, but with age this clearance becomes impaired. The signaling of senescent cells, useful in the short term, becomes disruptive to tissue function and structure when sustained over the long term by a growing population of lingering senescent cells.
While much of the research and development of anti-senescence therapies involves the production of senolytic treatments that can selectively destroy these cells, there is some interest in trying to find ways to suppress the harmful signaling of of senescent cells instead. This seems likely to be more challenging and less effective as a strategy, as the regulation of the senescent state is complex, and any one intervention is likely to only affect a modest fraction of the whole. Nonetheless, see today’s open access paper as an interesting example of the research taking place into means to reduce senescent cell signaling. Unlike most such research at the present stage of development, the authors did actually test their work in mice, and demonstrated a small extension in life span to result from their approach to suppression of senescent cell signaling.
PKM2 aggregation drives metabolism reprograming during aging process
Aging is a progressive process characterized by the systemic deterioration of organs and tissues, often culminating in chronic diseases such as diabetes, cancer, cardiovascular disorders, and neurodegenerative diseases. In recent years, the disruption of proteostasis has emerged as a well-recognized hallmark of aging. It is principally guarded by the chaperone-mediated folding system and degradation pathways involving lysosomes or proteasome. Dysfunction in either of these systems can precipitate the accumulation of aberrant protein aggregates within cells, thereby contributing to the onset and progression of aging-related pathologies.
In this study, we conducted an analysis of lysosomal proteomics from young and senescent cells, leading us to uncover the role of Pyruvate Kinase M2 (PKM2) aggregates in the aging process. In senescent cells, PKM2 tends to aggregate along with other glycolytic enzymes, such as Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), α-Enolase (ENO1), and others. Furthermore, we found that PKM2 aggregation accompany with impairment of PKM2 enzymatic activity and glycolytic flux in senescent cells, exacerbating senescent phenotypes.
To identify compounds capable of dissolving PKM2 aggregates and alleviating senescence, we conducted a series of screenings. K35 and its analog K27 were identified as compounds capable of inhibiting the formation of PKM2 aggregates. Treatment with K35 or K27 restored PKM2 enzymatic activity and glycolytic flux. Further studies demonstrated that K35 or K27 not only alleviated cellular senescence but also extended the lifespan of both naturally and prematurely aged mice.
