Sci. Aging Knowl. Environ., 29 September 2004
Vol. 2004, Issue 39, p. pe36
[DOI: 10.1126/sageke.2004.39.pe36]

PERSPECTIVES

Ras: The Other Pro-Aging Pathway

Valter D. Longo

The author is in the Andrus Gerontology Center and Department of Biological Sciences at the University of Southern California, Los Angeles, CA 90089, USA. E-mail: vlongo{at}usc.edu

http://sageke.sciencemag.org/cgi/content/full/2004/39/pe36

Key Words: Ras • Akt • insulin/insulin-like growth factor-1 • chronological aging • yeast

Introduction

Analogously to multicellular organisms, unicellular yeast age chronologically (1). In yeast as well as in higher eukaryotes, chronological life span represents the age of the organism at death. The number of times that a mother cell buds to produce daughter cells in its lifetime represents a different measure of life span in yeast: the replicative life span (2, 3) (see Kaeberlein Perspective). The progressive accumulation of ribosomal DNA circles in the nucleolus may be the cause of replicative aging (4). By contrast, chronological aging is mediated in part by superoxide generated by the mitochondria and is preceded by the loss of mitochondrial function (5, 6).

Aging-related research in worms and flies points to the involvement of the insulin/insulin-like growth factor-1 (IGF-1) pathway in the regulation of life span (see Johnson Subfield History and Warner Subfield History). This signal transduction pathway includes an IGF-1-like receptor, phosphatidylinositol 3-kinase (PI3K), members of the Akt/protein kinase B (PKB) family of kinases, and a forkhead transcription factor (Fig. 1). In yeast, chronological life span is regulated by Sch9, a serine-threonine kinase homologous to Akt (5) (see Fabrizio Science article). However, another signal transduction pathway regulated by Ras2 and partially independent of Sch9 also controls both stress resistance and life span in yeast. Ras2, together with the closely related protein Ras1, are the yeast homologs of the mammalian proto-oncogene protein Ras. They are small GTP-binding proteins (G proteins) that alternate between active GTP-bound and inactive GDP-bound forms. Mutations in yeast that reduce the activity of various components of the Ras/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway extend chronological life span (5, 6). Ras and Sch9 function in overlapping but distinct pathways that mediate glucose-dependent signaling, stimulate growth and glycolysis, and decrease stress resistance (7-9). The slow growth phenotype of yeast lacking Sch9 is reversed by the expression of human Akt, indicating that human Akt can functionally substitute for Sch9 in yeast (10). This observation suggests that components of an IGF-1-like pro-aging pathway might be conserved from yeast to mammals (11, 12). However, it is not clear whether Sch9 is the homolog of Akt itself or of other members of the PKB family of serine-threonine kinases. In fact, Caenorhabditis elegans serum- and glucocorticoid-inducible kinase (SGK-1), which has approximately 55% sequence similarity to Akt, appears to play a more important role than Akt in longevity regulation in C. elegans (13).



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Fig. 1. Conserved regulation of longevity. In yeast, worms, and flies, the partially conserved glucose or insulin/IGF-1-like pathways down-regulate antioxidant enzymes and heat shock proteins, reduce the accumulation of glycogen or fat, and increase growth and mortality. Mutations that reduce the activity of these pathways extend longevity by simulating genes expressed during periods of caloric restriction or more severe forms of starvation. In yeast and worms, the induction of stress resistance genes is required for longevity extension. In mammals, IGF-1 activates signal transduction pathways analogous to the longevity regulatory pathways in lower eukaryotes and increases mortality. However, the intracellular mediators of life-span extension in growth hormone (GH) or IGF-1-deficient mice have not been identified. In humans, mutations or diseases that result in plasma GH or IGF-1 deficiencies cause dwarfism, obesity, and other defects, but their effect on longevity is unclear (see "Power to the People"). Hsps, heat shock proteins; PtdIns-3-Ps, phosphatidylinositol 3-phosphates.

 
Ras Signaling and Stress Resistance in Yeast

Ras1 and Ras2, which function directly upstream of adenylate cyclase (Cyr1, an enzyme that catalyzes the production of cAMP from adenosine triphosphate) in the Ras/cAMP/PKA pathway, play overlapping roles in cell growth, development, and stress resistance in yeast (14-16). Actively dividing ras2-null (ras2{Delta}) mutant yeast cells resemble wild-type cells that have entered a long-term survival phase (stationary phase) in that they accumulate glycogen and have increased thermotolerance and antioxidant defenses. The increased stress resistance displayed by ras2 mutants as compared to the wild type is caused in part by the induction of transcription factors Msn2 and Msn4, which are inactivated in wild-type cells by PKA (17) downstream of Ras. Msn2 and Msn4 regulate the transcription of a number of genes that contain the stress response element (STRE) in their promoters (18). Among the genes regulated in this manner are those encoding several heat shock proteins and catalase (CTT1) as well as the DNA damage-inducible gene DDR2 (18) and genes involved in the storage of reserve nutrients (19). The expression of superoxide dismutases (Sods) might also be regulated by Msn2 and Msn4. This idea is supported by the observations that (i) the SOD promoters each contain an STRE sequence and (ii) the level of expression of SOD2 in a strain that lacks RAS2 is doubled relative to the level of expression in the wild type (20). The Ras/cAMP/PKA pathway down-regulates the activity of the protein kinase Rim15 which, in turn, activates the stress resistance transcription factor Gis1 (21). Similarly to Msn2 and Msn4, Gis1 regulates stress resistance through a specific sequence (the "post-diauxic shift" element) contained in the promoter of genes including HSP26, HSP12, and SOD2 (20, 21). Thus, the expression of SOD2 may be regulated by both Msn2/Msn4 and Rim15/Gis1.

Ras and Replicative Aging in Yeast

Early studies suggested that Ras plays opposite roles in the regulation of chronological and replicative life span. The overexpression of either the v-Ha-RAS oncogene or Ras2 extends the yeast replicative life span relative to that of the wild type (22, 23). Induction of RAS2 transcription causes a 20 to 40% increase in the mean and maximum replicative life span. However, the role of the Ras pathway in the regulation of replicative aging is controversial, because studies by other researchers show that the deletion of RAS2 causes a small increase in replicative life span, whereas its constitutive expression drastically decreases replicative potential (24). Lin et al. also showed that the mutations that down-regulate the Ras/cAMP/PKA pathway extend replicative life span (25). Furthermore, Hlavata et al. showed that the constitutive activation of Ras2 by the RAS2val19 mutation increases the generation of toxic oxygen species and reduces replicative life span (26). However, the effect of low Ras/cAMP/PKA activity on replicative life span might be independent of age-dependent deterioration and loss of function, considering that the stress resistance transcription factors Msn2 and Msn4 are not required for its effect on replicative longevity (25). In fact, deletion of both MSN2 and MSN4 extends replicative life span (27). Furthermore, two studies showed that increased protection against superoxide toxicity, which increases chronological survival, actually decreases replicative life span (27, 28).

Ras and Chronological Aging in Yeast

The discovery of the role of Ras, adenylate cyclase, PKA, and Sods in the regulation of stress resistance and longevity in yeast (6, 29-31), together with the discovery of the role of the IGF-1-like pathway in aging in C. elegans (12, 32, 33), provided the first descriptions of pathways that control chronological aging in eukaryotes (6, 29-31). The deletion of RAS2, which is highly conserved in many organisms and functionally interchangeable between human and yeast cells, increases Sod activity and resistance to paraquat (an herbicide that causes oxidative stress) and doubles the average longevity of two yeast strain backgrounds (DBY746 and SP1) (Fig. 2) (6, 29, 30). In contrast, constitutive activation of Ras (RASval19) causes a major decrease in life span (Fig. 2) (6, 29). As stated above, Ras2 functions directly upstream of adenylate cyclase, and inactivation of this enzyme by a temperature-sensitive mutation in the CYR1 gene increases chronological life span (Fig. 2) (6, 29). Furthermore, transposon insertions in CYR1 extend life span (5), confirming the involvement of the Ras pathway in longevity regulation. Consistent with a pro-aging role of the Ras/cAMP/PKA pathway, constitutive activation of PKA causes a large decrease in chronological survival (29).



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Fig. 2. Ras inactivation extends life span in yeast. The chronological life span (percent survival) is shown for (A) the wild type (strain SP1, solid symbols) and ras2{Delta} (open symbols); (B) the wild type (strain DBY746) and ras2{Delta}; (C) the wild type (SP1) and ras1{Delta}ras2ts (lacking RAS1 and containing a temperature-sensitive mutation in RAS2); and (D) the wild type (SP1) and RAS2val19 mutants that express constitutively active Ras2. [(A) has been reproduced from (6) with permission]

 
Longevity extension in both the ras2 and cyr1 mutants requires the stress resistance transcription factors Msn2 and Msn4 and the mitochondrial superoxide dismutase Sod2, suggesting that increased investment in protection and repair slows down aging (5, 6). Furthermore, the strong age-dependent inactivation of the superoxide-sensitive enzyme aconitase that occurs in wild-type cells is delayed by mutations that affect the Ras pathway and by overexpression of both Sods (SOD1 and SOD2) (5, 6). These studies indicate that Ras promotes aging in part by shifting energy investment from protection and replacement to growth.

Ras, Stress Resistance, and Cell Death in Mammalian Cells

The similarities between the pathways that regulate stress resistance and longevity in yeast, worms, and flies (Fig. 1) suggest that analogous mutations might also affect cellular protection and aging in mammals. Interestingly, the four yeast genes found to have the most profound effect on yeast chronological life span, SOD1, SOD2, RAS2, and SCH9, are highly conserved from yeast to humans and, in each case, can be functionally replaced by their mammalian homologs (5, 10, 13, 31, 34). Whether mutations in genes encoding G proteins affect mammalian longevity is a question that has not been addressed at the organismal level, although several studies in mammalian cells suggest that Ras activity might contribute to aging. (In these systems, Ras is sometimes referred to as p21Ras, indicating the mass of the protein.) Neuronal apoptosis increases in mice lacking a negative regulator of Ras (35), whereas inhibition of p21Ras rescues na�ve (undifferentiated) and neuronally differentiated PC12 cells from apoptotic death (36). The PC12 cell line is derived from the rat adrenal medulla; these cells undergo terminal differentiation when they are treated with nerve growth factor. The inhibition of p21Ras in PC12 cells increases resistance to oxidative stress (37) and survival after serum withdrawal from the medium (36). Inhibition of p21Ras in PC12 cells also prevents superoxide generation induced by treatment with epidermal growth factor (EGF, which normally stimulates the Ras pathway) (38). Ras also mediates apoptosis in T cells (39) and in human epithelial cells (40) and induces replicative senescence in human diploid fibroblasts by increasing intracellular concentrations of reactive oxygen species (41).

In addition to promoting cell growth and cell death, Ras activation can prevent cell death, as shown for rat sympathetic neurons (42) and endothelial cells (43). Activation of Ras may cause or prevent cell death, depending on the activity of other signal transduction pathways and on the relative activity of downstream proteins such as mitogen-activated protein kinase (MAPK), Rac1, and PKB, which have been implicated in both proapoptotic and antiapoptotic signaling. These apparently contradictory pro- and anti-aging effects of Ras might be explained by the fact that the inhibition of apoptosis is required during phases of growth or to perform certain functions that either involve oxidants as signaling molecules or at least require high respiratory rates and therefore high generation of oxidants. Thus, under certain conditions, Ras might prevent apoptosis to promote cell growth and function while inducing cell damage and aging. Whereas in a young organism Ras-dependent damage might be repaired efficiently, a chronic Ras-dependent increase in the generation of oxidants and decrease in protection against damage could accelerate aging and contribute to multiple age-related diseases.

Ras in the IGF-1 Pathway

The similarities between the glucose- or IGF-1-like signaling pathways that regulate life span in yeast, worms, and flies suggested that the mammalian IGF-1 pathway might also play a central role in the aging rate. In fact, mice with mutations that reduce plasma IGF-1 concentrations and mice with lower than normal IGF-1 activity live considerably longer than the wild type (44, 45) (see Bartke Viewpoint, Quarrie Review, and "One for All"; as well as genetically altered mice entries Ames Dwarf, Snell Dwarf, Little Mice, Laron Mice, and IGF-1R+/– Mice). Although the intracellular mediators of this effect of IGF-1 on longevity have not been identified, the Ras and PI3K/Akt pathways are major candidates, considering their primary role in IGF-1 signaling (Fig. 3) (46). After IGF-1 binding to its receptor, Ras binds to GTP and activates the RAF/MEK/ERK as well as the SEK/p38 and other pathways involved in many functions, including cell growth, differentiation, and apoptosis. One possible link between Ras activity and longevity in mammals is provided by the discovery of the pro-aging role of p66shc, a protein that is tyrosine-phosphorylated upon activation of growth factor receptors and binds to Grb2, an adaptor protein for the Ras guanine nucleotide exchange factor SOS. A targeted mutation of p66shc in mice (to create p66shc–/– Mice) increases stress resistance and prolongs life span (47) (see Martin Perspective). Although p66shc is not required for the activation of the Ras/MAPK pathway by EGF (48), it is not known whether it functions downstream of IGF-1 or upstream of Ras to affect life span.



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Fig. 3. The Ras and Akt pathways in IGF-1 signaling. 4EBP1, eukaryotic translation initiation factor 4E binding protein 1; eIF4E, eukaryotic translation initiation factor 4E; ERK, extracellular signal-regulated kinase; GRB2, growth factor receptor-bound protein 2; IGFBP, IGF-binding protein; IRS1, insulin receptor substrate 1; MEK, mitogen-activated protein kinase kinase; PIP, phosphatidylinositol; PTEN, phosphatase and tensin homolog; S6K, S6 kinase; SHC, SRC homology 2-domain transforming protein; SHP2, PI3K regulatory subunit; SRF, serum response factor; TOR, target of rapamycin. [Reproduced from (46) with permission from Nature Publishing Group]

 
Conclusions

The discovery of life span-extending mutations that affect similar pathways in yeast, worms, and flies suggests that many eukaryotes can delay aging and death by activating a set of stress resistance/repair/replacement genes that are normally activated during periods of starvation. In fact, calorie restriction has been shown to extend longevity in many organisms (49) (see Masoro Subfield History). The yeast and worm longevity regulatory pathways share remarkable similarities and include members of the PKB family of serine-threonine kinases as well as stress resistance transcription factors that control the expression of antioxidant enzymes and heat shock proteins. A similar pathway that includes an IGF-1-like receptor, Akt, and a stress resistance transcription factor is implicated in longevity regulation in flies (50) (see Antebi Perspective). In contrast, a Ras-dependent pathway has only been shown to control life span in yeast. The role of IGF-1 and IGF-1 signaling in the regulation of the mouse life span, together with the central role of the Akt and Ras pathways in IGF-1 signaling, suggest that these two pathways might also regulate stress resistance and aging in mammals. It will be important to understand how and why these intracellular pathways affect cellular damage, apoptosis, and aging. Simple model systems such as yeast can reveal fundamental mechanisms that control longevity and allow the identification of the key regulators of the "switch" from a shorter-lived growth mode to a long-lived starvation-response mode. However, it will be challenging to determine how these and other signal transduction pathways can be modulated to delay aging and age-related diseases without affecting normal function in mammals. In fact, Ras, Akt, and Sgk-1 might accelerate aging in certain or all cells but at the same time play essential or important roles in functions such as growth and metabolism. Notably, mice lacking serum IGF-1, flies deficient in IGF-1-like signaling, and yeast lacking the Akt/PKB homolog Sch9 are long-lived but much smaller in size as compared to the wild type, but yeast lacking RAS2 and worms with certain mutations in daf-2, which encodes an insulin-like/IGF-1 tyrosine kinase receptor, are long-lived but reach normal sizes (11).


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Citation: V. D. Longo, Ras: The Other Pro-Aging Pathway. Sci. Aging Knowl. Environ. 2004 (39), pe36 (2004).




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