Metabolic stress, defined here as a combination of aerobic glycolysis and mitochondria dysfunction can potentially trigger a senescent state. All organisms that use aerobic glycolysis form reactive acyclic α-oxoaldehydes (e.g. methylglyoxal and glyoxal) spontaneously from triosephosphates and by a wide variety of other routes (Thornalley, 2009). These dicarbonyl compounds are highly reactive and damage proteins through non-enzymatic modification producing a wide variety of covalent adducts (AGEs). Elevated levels of methylglyoxal and glyoxal are known to be cytotoxic and although the mechanism of action remains imprecisely defined, it can be blocked by ROS scavengers, suggesting that oxidative stress mediates at least some of the deleterious effects (Shangari and O’Brian, 2004).
Cytosolic and mitochondrial protection from dicarbonly damage is primarily mediated through the action of the glyoxalase system that consists of two enzymes, glyoxalase I and II. However, in cultures of WI38 fibroblasts a significant reduction in the activity of glyoxalase-I occurs with serial passage (Ahmed et al. 2010). Treatment of cultures of ASF2 human adult dermal fibroblasts with micro or millimolar concentrations of glyoxal or methylglyoxal renders them senescent within 72 hours. This was defined by the presence of typical senescent morphology, irreversible growth arrest and increased SA-β-Gal activity (Sejersen & Rattan, 2009). Further studies (Larsen et al. 2012) extended these observations to immortalized human mesenchymal stem cells (MSCs) and demonstrated that treatment with physiologically reflective (Han et al. 2007) concentrations of glyoxal for 72 hours led to senescence without significant cell death (although massive cell death occurred at higher glyoxal concentrations). Elevated levels of SA-β-Gal, p16 and DNA damage (as measured by COMET) accompanied the growth arrest. Interestingly, a profound reduction in the ability of these senescent MSCs to differentiate into functional osteoblasts (as determined by alkaline phosphatase and mineralization assays) was also observed. Given the imbalances in glucose metabolism that accompany mammalian ageing (and diabetes), the authors proposed that this type of metabolic stress might underlie age-related changes in bone function. Unfortunately, no markers of immunogenic conversion have yet been measured in this system and whilst the presence of DNA damage could indicate the likelihood of a secretory response, this cannot be assumed. Thus, the propensity of senescence human MSCs to be cleared by the immune system remains unknown and is of considerable physiological significance.