Mitochondrial dysfunction, increased lipid peroxidation and altered catabolism will affect the cellular lipidome during cell senescence. Alterations in lipid metabolism and the generation of oxidised lipids may be beneficial for the senescent program during the early stages of senescence induction, possibly through modulating inflammatory and immune responses (Lawrence et al. 2002; van Diepen et al. 2013; Yaqoob 2003). However, if senescent cells persist in tissues, changes in lipid composition can result in cell dysfunction, altered rates of fatty acid oxidation that can induce inflammation and increased lipid peroxidation that can promote damage to neighbouring cells. These factors may contribute to ageing and age-related diseases. Research focused on altered lipid metabolism during cellular senescence, particularly regarding mitochondrial lipids, is in its infancy. However, in recent years, several studies have made progress in evaluating the senescent lipidome of fibroblasts.
One group investigated the alterations in a number of metabolites associated with the extracellular metabolome of fibroblasts induced to senesce via proliferative exhaustion or via γ-irradiation (James et al. 2015). They reported that a number of fatty acids and their precursors such as eicosapentaenoate, malonate, 7-alpha-hydroxy-3-oxo-4-cholestenoate and 1-stearoylglycerophosphoinositol were elevated during fibroblast senescence when compared with proliferating and quiescent cells, whereas linoleate, dihomo-linoleate, 10-heptadecenoate were depleted. Also amongst the secretory lipidome from senescent fibroblasts was an accumulation of monohydroxy fatty acids (2-hydroxypalmitate, 2-hydroxystearate, 3-hydroxydecanoate, 3-hydroxyoctanoate) and a phospholipid catabolite (glycerophosphorylcholine). It was suggested that whilst some of these changes may be due to oxidative stress, other observed increases may be a response to increased biomass commonly observed amongst senescent cells.
Maeda et al. (2009) investigated the regulation of fatty acid synthesis and ∆9-desaturation during cell senescence in human fibroblasts (Maeda et al. 2009). They found that the levels of fatty acid synthase and stearoyl-CoA desaturase-1 were decreased in senescent fibroblasts compared to proliferating fibroblasts, consequently leading to a decrease in monounsaturated fatty acids. In addition, reduced de novo synthesis of phospholipids with an associated increase in the formation of cholesterol in senescent cells was also observed and exogenous fatty acids were shown to be preferentially incorporated into the triacylglycerol pool of senescent cells.
In another study, the metabolic alterations associated with oncogene-induced senescence (OIS), using Ras-induced senescent human fibroblasts as a model were investigated (Quijano et al. 2012). Through the profiling of ~300 different intracellular metabolites, these authors showed that cells that have undergone OIS develop a metabolic signature which is distinct from cells which have undergone replicative senescence in response to extended in vitro cell culture. In the latter, a switch towards glycolysis has been observed that precedes the onset of senescence (Bittles and Harper 1984). In OIS, an increase in certain intracellular long chain fatty acids, including eicosanoate, dihomo-linoleate, mead acid and docosadienoate were observed. This altered metabolome was shown to associate with a decline in lipid synthesis and increases in fatty acid oxidation. Interestingly, the pro-inflammatory activity of the senescent secretome was reduced by inhibition of carnitine palmitoyltransferase 1, the rate limiting step in mitochondrial fatty acid oxidation, suggesting that alterations in lipid metabolism during OIS may play a role in regulating the pro-inflammatory senescent secretome. Although the mechanism underlying the increase in fatty acid levels during OIS were not fully explored, it may be due to promyelocytic leukemia (PML) activation of the fatty acid oxidation pathway through PPAR signalling (Aird and Zhang 2014). The differences between replicative senescence and OIS are intriguing; they may relate to the physiological need in preventing cancer to switch away from glycolysis as a rapid source of energy that is harnessed by cancer cells to enable them to proliferate rapidly versus the increasing insulin resistance that is seen in ageing and which associates with impaired oxidative metabolism (Burkart et al. 2016). However, while this and other studies have indicated an increase in glucose uptake during OIS, a number of other studies have observed either no change or a significant decrease in glucose uptake. This may relate to the timing of senescence induction, the cell type or the oncogene responsible.
A further study compared global lipid profiles and associated mRNA levels of proliferating and replicative senescent BJ fibroblasts; 19 specific polyunsaturated triacylglycerol species were identified as undergoing significant changes in lipid composition during cell senescence (Lizardo et al. 2017). In addition, significant changes in the expression of genes involved in specific lipid-related pathways, including glycerolipid metabolism, glycerophospholipid metabolism, unsaturated fatty acid synthesis and sphingolipid metabolism were observed during cell senescence. Based on these lipidomic and transcriptomic analysis, the authors postulated that activation of CD36-mediated fatty acid uptake and alteration to glycerolipid biosynthesis may contribute to the accumulation of triacylglycerols during cell senescence. It was suggested that these changes may be a mechanism to prevent lipotoxicity during elevated oxidative stress conditions during cell senescence.
In addition to an altered lipidome during cellular senescence, elevated ROS, likely from uncoupled mitochondria, can promote lipid peroxidation which potentiates cellular damage at distant sites. For example, stable aldehydes can diffuse from their site of generation and form adducts at distant locations, thereby propagating the responses and injury initiated by ROS (Ramana et al. 2013), including the induction of cell senescence in neighbouring cells. Flor and Kron observed an accumulation of lipid-derived aldehydes such as 4-hydroxy-2-nonenal (4-HNE) during accelerated senescence (Flor and Kron 2016). Whereas, the treatment of cells with either 4-HNE or low (5 Gy) γ-irradiation only generated low levels of cell senescence, combining both 4-HNE and 5 Gy γ-irradiation significantly elevated the senescence response. Furthermore, the use of the aldehyde-sequestering drug hydralazine blocked cell senescence induction by 25 Gy and etoposide treatment, demonstrating the potential importance of lipid peroxidation during therapy-induced senescence (Flor et al. 2016). Despite the highly damaging and pro-ageing potential of senescence-derived lipid peroxidation, little research has been conducted in this area and this requires further study.
Research on cell senescence has primarily been undertaken on fibroblasts and more research is required to explore whether the same phenomena are observed in cell-types linked to age-related disease such as in senescent adipocytes, pancreatic beta cells, renal proximal tubular epithelial cells and vascular endothelial cells. Whilst different types of senescent cells may share similarities in lipid metabolism, there may also be differences that are cell type-dependent or due to the mechanism of senescence induction and these require further study to better assess the role of altered lipid metabolism during ageing and disease. Finally, an important question to contemplate is whether the alterations in ROS, lipid metabolism and mitochondrial lipids observed during ageing and diseases are due solely to the presence of senescent cells or whether lipidomic changes can occur in absence of senescent cell accumulation.
