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.
