There exist several starvation scenarios: nitrogen, amino acid, carbon and complete starvation, the latter one being a shift of the cells into water. Initially, starvation studies in yeast led to the paramount discovery and characterization of the autophagy-related genes (ATG
s). Starvation is also used as a model for caloric restriction and aging studies [34,35]
. Shifting yeast cells into starvation conditions results in longevity in many cases [35,36]
. This long-lived cells show changes in their metabolism, autophagy rates, stress response, cell division, as well as in the quality and quantity of organelles (e.g. mitochondria) (). Longevity is also associated with changes in protein levels, caused by altered transcription, posttranscriptional modification, turnover or translocation. Of note, exogenous media change can impact longevity by changing the intracellular metabolite pattern. The identification of aging-related metabolites and the mechanisms of how energy metabolism connects to various starvation-induced pathways are pivotal to understand how caloric restriction exerts its beneficial effects on stress response and longevity.
Autophagy (a cellular self-digestion process) is a suggested key component of longevity that is crucial for metabolic homeostasis. Recent studies with life span-extending deletion strains (e.g. such deleted in the target of rapamycin TOR1
or the protein kinase SCH9
) have revealed overlapping activities of autophagy and nutrient-responsive stress response pathways in the context of longevity [35,37]
. Moreover, autophagy-stimulating substances (resveratrol, rapamycin and spermidine) have been shown to elongate life span or health span from yeast to mammals in an autophagy-dependent fashion [38–41]
. ROS is known to shorten chronological life span, and superoxide in particular was suggested to play important signaling roles during aging [36,42]
. However, early sublethal concentrations of ROS can strengthen the cell and lead to life span extension, a process often referred to as hormesis [43,44]
. Under nitrogen starvation conditions, accumulation of mitochondrial H2
is essential for autophagy induction. Here, the oxidative environment of mitochondria inhibits the activity of Atg4p by oxidizing a regulatory cysteine residue, which inhibits delipidation of a further protein essential for macroautophagy, Atg8p, thus allowing autophagosome formation. Away from mitochondria, a reducing environment around the vacuole/lysosomes is maintained, where Atg4p can cleave Atg8p from autophagosomes, a process required for the fusion with the vacuole/lysosomes 
. Since starvation and aging share overlapping pathways for survival maintenance, it is a pivotal yet pending matter to understand the mechanistic relationships between sublethal hormetic and autophagy-inducing oxidative stress, versus the detrimental consequences of high ROS levels.
As mentioned above, loss of viability was initially used to screen for autophagy-defective mutants in S. cerevisiae
; however, the mechanism of cell death in these mutants has remained unclear. Suzuki and colleagues (2011) were able to show that, upon starvation, wild type cells upregulate proteins for respiration and ROS-detoxifying enzymes. In contrast, ATG-
depleted cells lack this adaptive detoxifying process and consequently accumulate high levels of ROS. This leads to a deficiency in the respiratory function, resulting in the loss of mitochondrial DNA and further cell death 
. Mitochondria are believed to be one of the main sources of ROS and therefore it seems logical that by removing mitochondria, cell death can be prevented under conditions where respiration is not essential to meet the cell's energy demand. The role of autophagy as a clearing mechanism, which also eliminates damaged mitochondria, has been demonstrated, but a special role for selective mitophagy has not been confirmed 
. Cells deleted in ATG32
, which is essential for selective mitophagy, showed nearly normal respiratory activity, indicating that selective mitochondria-elimination is not responsible for the observed respiratory defects caused in ATG
deletion strains under starvation conditions. On the other hand, cells lacking ATG15
, which can form autophagosomes but not degrade their contents, led to respiratory-deficient cells.
Several studies in recent years have shown that the nutritional signaling pathways involving the kinases Akt/PKB, Tor and Ras regulate life span of several model organisms, suggesting that the underlying mechanisms of longevity are conserved among eukaryotes 
. These kinases are part of nutrition and growth factor sensing pathways and control many aspects of cell physiology, including ribosome biogenesis, translation, autophagy, cell growth, and proliferation 
, and suppress the activity of cellular stress responses (e.g. mediated by transcription factors). It was shown in yeast, that both Ras2p and Tor1p influence key anti-stress regulators, such as the protein kinase Rim15p, the transcriptional activator Msn2/4p, and the histone demethylase/transcription factor Gis1p (). These factors directly or indirectly increase the levels of detoxification enzymes (e.g. Sod2p) and protein chaperones (e.g. heat shock proteins) 
. Moreover, besides regulating stress-resistance genes, Ras also directly regulates mitochondrial respiration and ROS production 
. Upon starvation, pharmacological treatment (e.g. rapamycin) or gene deletion, the inhibition of these pathways leads to activation of the key transcription factors enhancing stress defense and longevity. Although many reports have linked these pathways to aging [49,50]
, the mechanisms of caloric restriction-dependent life span extension remain poorly understood. Recently, Wei and colleagues (2009) identified expression changes in a set of genes controlled by Sch9p as well as Tor1p and Ras2p that caused a metabolic switch, which together with the direct regulation of stress resistance was responsible for enhanced cellular protection and life span extension 
. This metabolic switch resulted in a shift from respiration to glycolysis, causing the removal of pro-aging carbon sources (e.g. glucose) as well as glycerol biosynthesis. Consistently, strains deleted in either Sch9p, Tor1p or Ras2p (mimicking starvation) displayed an up-regulation of genes involved in glycolysis/fermentation, while mitochondrial related genes were down-regulated. As a consequence, mitochondrial function including the TCA cycle and oxidative phosphorylation was diminished and further inhibited generation of ROS 
. Accordingly, it was hypothesized by Ruckenstuhl et al. (2010) that the glycolytically generated NADH, not used for respiration, is redirected and used for production of glycerol, a scenario normally taking place under anaerobic conditions 
. New insights into Tor1p-regulated mitochondrial function during growth and in the postdiauxic stationary phase have been provided by Pan et al. (2011). Their study shows that elevated ROS (e.g. superoxide) in TOR1
deletion strains during growth is an adaptive mitochondrial signal that programs the down-regulation of mitochondrial potential and ROS during stationary phase to promote longevity. They also confirmed a role of media metabolites (e.g. acidification), but proposed a mostly intrinsic control of longevity-related pathways 
In order to understand the process of aging, age-related disorders like neurodegeneration and lifestyle-associated diseases like diabetes/stroke, it is important to consider the actual metabolome and the respective anabolic and catabolic activities of a cell in addition to simply analyzing pathway activities.