Sci. Aging Knowl. Environ., 11 August 2004
Vol. 2004, Issue 32, p. pe32
[DOI: 10.1126/sageke.2004.32.pe32]

PERSPECTIVES

Ticking Fast or Ticking Slow, Through Shc Must You Go?

Florent M. Martin, and Jeffrey S. Friedman

The authors are in the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. E-mail: friedman{at}scripps.edu (J.S.F.)

http://sageke.sciencemag.org/cgi/content/full/2004/32/pe32

Key Words: p66shc • insulin-like growth factor • p53 • mitochondria • heat shock protein

Introduction

The number of genes implicated in the control of aging is rapidly multiplying. A recent version of the SAGE KE Genes/Interventions database, for example, lists 86 genes in Caenorhabditis elegans, 24 genes in Drosophila, and 8 genes in mice that confer extended longevity when altered (the list includes a combination of null, hypomorphic, gain-of-function, and overexpressor alleles) and an equally impressive number of genes identified in human cell culture or yeast studies that, when mutant, alter phenotypes thought to be analogous to aging. But wait! That's not all... RNA interference studies in C. elegans suggest that as many as 1 in 50 genes exert a measurable negative impact on longevity (when expressed at wild-type levels) (see Melov Perspective), so the list will likely continue growing. Classifying or integrating this growing number of "longevity-influencing" genes into a few fundamental "longevity-determining" pathways will warm the hearts of those who value simplicity and might even afford the field its own chapter in basic biology texts! Integration is also needed to reconcile the lists of genes that come from studies of isolated cells or tissues with genes identified as affecting animal longevity. In this Perspective, we review interactions between the p66shc, p53, and insulin-like growth factor-1 (IGF-1)/Daf pathways and present possible ways for integrating these pathways, which have been show to affect both cellular phenotypes and longevity in mammals.

Slowing Down the Clock in Mice

There is a growing body of evidence that a conserved signal transduction pathway analogous to the mammalian IGF pathway is a regulator of aging in C. elegans, Drosophila, mice, and presumably other mammals, including primates (1). Mammals possess several insulin-like pathways, including the insulin/insulin receptor pathway that controls glucose homeostasis and the growth hormone (GH)/GH receptor and IGF-1/IGF-1 receptor (IGF-1R) pathways that both regulate growth. Two spontaneous lines of dwarf mice, Ames (homozygous for the Prop1df mutation) and Snell (homozygous for the Pit1dw mutation) that have deficiencies of GH, prolactin, and thyroid hormone are long-lived (2, 3), as are mice lacking the GH receptor (GHR/BP) (Laron mice) (4). Each of these lines, as a consequence of loss of GH production or loss of GH activity, has profoundly low levels of IGF-1 (see Bartke Viewpoint and Quarrie Review). Low IGF-1 concentrations are also characteristic of mice maintained on low-calorie diets (see "Dieting Dwarves Live It Up"), a manipulation that also extends longevity (see Masoro Subfield History), providing indirect evidence that signaling through the IGF-1R pathway would control longevity in mammals.

Direct support for such a hypothesis comes from a hypomorphic mutation in the IGF-1 signaling pathway in mice created by knockout of the gene encoding the IGF-1R (IGF-1R) (5). Mice that are IGF-1R-null die at birth, but mice that are haploinsufficient for IGF-1R develop normally, have normal fertility, and have an extended life span (33% longer for females, 16% longer for males) (see "One for All"). Unlike dwarf mice, IGF-1R+/– animals maintain a normal body temperature, maintain caloric intake equivalent to that of control mice, have a similar mean metabolic rate when compared to control animals, and have only a slight decrement in weight (8% in males, 6% in females) that first appears after weaning and persists throughout life. IGF-1R+/– mice show resistance to challenge with paraquat (a compound that induces oxidative stress) when compared to control animals, and IGF-1R+/– embryonic fibroblasts (MEFs) are resistant to hydrogen peroxide when compared to wild-type MEFs. As expected, signal transduction in response to IGF-1 is reduced in IGF-1R+/– fibroblasts, with decreased tyrosine phosphorylation of receptor substrates and consequent decreased recruitment of adapter proteins and reduced activation of more distal components in the signaling cascade.

Shc proteins, including p66shc (also known as p66Shc or p66), are among the downstream components that become phosphorylated upon IGF-1R activation, and IGF-1R+/– cells show decreased tyrosine phosphorylation of p66shc (5). This result is of interest because mice that lack p66shc are also long-lived and demonstrate resistance to oxidative stress (6). However, the significance of this finding as an explanation for the longevity phenotype in IGF-1R+/– mice has not yet been thoroughly examined. For example, experimental evidence demonstrates that phosphorylation of a serine residue near the amino terminus of p66shc is required for transduction of oxidant stress signals, but whether phosphorylation at this residue is required for the extended life span displayed by IGF-1R+/– mice has not yet been tested.

Further analysis of IGF-1R+/– mice will also be required to gain a better understanding of how the insulin-like signaling pathway is affected in this mutant. For instance, mutation of the gene encoding the insulin/IGF-R in C. elegans (DAF-2) results in increased activity of a FOXO forkhead transcription factor (DAF-16), an activity that is required for the increased life span of daf-2 mutants. Whether the increased longevity of IGF-1R+/– mice is also dependent on the activity of a forkhead transcription factor remains to be elucidated.

Like worms that contain certain hypomorphic alleles of Daf pathway genes, IGF-1R+/– mice exhibit a significant increase in longevity, with little apparent trade-off in terms of reproductive function, metabolism, or robustness. As such, they represent an excellent mammalian phenocopy of a Daf pathway mutation and provide a murine model in which the rate of aging has arguably been slowed down. Such mutations will be important in determining the role (if any) of the "rate of aging" on the development of age-related diseases such as atherosclerosis or neurodegenerative diseases in mice developed as models of these human disorders.

Whereas only a subset of the longevity genes identified to date falls into the Daf pathway, there is a unifying characteristic of most, if not all, longevity mutants identified thus far, and that is enhanced resistance to stress, in particular resistance to oxidative stress (see, for example, Johnson Subfield History, Sampayo Perspective, and "Durable Dwarves"). In fact, stress resistance is intricately related to life span, as shown by experiments in C. elegans and Drosophila in which stress exposure early in life can lead to extended longevity (see "Stress for Success"), and animals selected for longevity show increased expression of stress-related genes (7-9) (see Larsen Perspective). Further experimentation has demonstrated that transgenic expression of particular stress-induced proteins, such as heat shock proteins (10-12) or the antioxidant proteins superoxide dismutase (SOD1; see also SOD2) and catalase (CAT) (13, 14) are sufficient to confer extended longevity in Drosophila. The importance of stress resistance genes, particularly those genes that protect cells from oxidant stress, in longevity provides support for the theory that oxidative damage is a major cause of aging (15, 16) (see "The Two Faces of Oxygen").

A direct role for forkhead proteins as mediators of oxidative stress resistance in mammalian cells has been demonstrated by studies showing transcription of a luciferase reporter gene driven by the catalase promoter upon addition of the active form of one of the forkhead transcription factors, FOXO3a (17) (see Nemoto and Finkel Science paper and "Stay Mellow, Stay Young"), and by demonstration that FOXO3a protects quiescent cells from oxidative stress in part through increasing transcription of manganese superoxide dismutase (18). A more nuanced view of how forkhead proteins mediate oxidative stress resistance and longevity has emerged from several recent papers that have employed microarray analysis (19, 20) or comparative genomics (21) to identify genes downstream of C. elegans DAF-16 (see Larsen Perspective). This picture includes induction of a broad range of stress response proteins such as catalase, superoxide dismutase, and heat shock proteins, but also indicates that repression of specific genes contributes to enhanced longevity, as do changes in protein turnover and metabolism.

A further insight from the array studies was that although activation of both DAF-16 and C. elegans heat shock transcription factor (HSF-1) extends longevity, each requires that the other protein be functional in order to extend longevity, and therefore are likely to coordinately regulate expression of a subset of genes critical for longevity (22) (see Hsu et al. Science paper and "Vital Collaboration"). DAF-16 activity, alone or in combination with HSF-1, has a dramatic effect on protein turnover in a model of age-dependent intracellular protein aggregation and deposition disease analogous to Huntington's disease (23). This result raises the possibility that modulation of the mammalian equivalent of the Daf pathway (the IGF-1 pathway) will have a similar effect on protein turnover and/or deposition in human disorders characterized by age-dependent protein deposition (both intracellular and extracellular) such as the amyloidoses, Alzheimer's disease, or Parkinson's disease.

Speeding Up the Clock in Mice

A direct role for p53 in mammalian aging

Evidence that the activity of the tumor suppressor p53 directly controls mammalian aging came from careful study of mice expressing an accidental truncation mutation (the result of gene targeting gone awry) of the p53 gene called the "m" allele (24). This allele encodes a truncated version of p53 (TRp53) containing exons 7 to 11, as well as a missense mutation in codon 245. In the presence of a normal p53 allele, the m allele enhances a variety of in vitro indices of p53 activity, including resistance of primary fibroblasts to transformation, response to DNA damage, and activation of genes that are transcriptional targets of p53. Mice carrying the m allele are highly resistant to tumor formation (2 out of 35 p53+/m mice developed tumors as compared to 27 out of 56 p53+/+ animals), but this resistance comes at a price: p53+/m animals have a median life span of 96 weeks, whereas p53+/+ littermates have a median life span of 118 weeks (a reduction of 23% for the p53+/m animals). For the majority of p53+/m animals at autopsy, no specific cause of death was noted; rather, the animals had a number of characteristics suggestive of accelerated senescence: weight loss, reduced organ mass and cellularity, osteoporosis, reduced dermal thickness, reduced subcutaneous fat, and muscle atrophy. In addition, p53+/m animals were found to be more sensitive than control animals to several stressors, displaying poor wound healing, anesthetic intolerance, and poor recovery from 5-fluorouracil-induced hematopoietic cell depletion. Thus, p53+/m mice exhibit a number of features consistent with an accelerated rate of aging, although this phenotype did not appear to affect all facets of aging; for instance, old p53+/m males retained equivalent fertility when compared to age-matched control animals, and no excess pathology was noted in the brain, liver, intestine, or blood in comparison with tissues from age-matched controls.

Similar findings (perhaps even more dramatic) were obtained by the creation of transgenic mice expressing a naturally occurring short isoform (called p44) of p53 that begins at an internal methionine at codon 41 of murine p53 (25) (see "Tumor-Free, But Not in the Clear"). Major characteristics of these mice include small size, decreased fertility, and early mortality (50% dead by 8 months for transgenic animals versus 50% dead by 24 months for nontransgenic mice). At a biochemical level, selected tissues from p44 transgenic mice as well as embryonic fibroblasts derived from these animals were shown to have alterations in the expression level and phosphorylation status of several components of the IGF-1 signal transduction cascade, suggesting that p53 modulates aging through interaction with the Daf/IGF-1 pathway. Somewhat confusing was the finding that mice heterozygous for the p44 transgene had an essentially wild-type phenotype, whereas mice homozygous for the transgene displayed the dramatic phenotype described. As with mice carrying the p53 m allele, biological activity of the p44 allele requires the presence of wild-type p53, because transgene-positive p53 null mice were indistinguishable from p53 null animals. Reminiscent of the Goldilocks fairy tale, the accelerated aging phenotypes observed in each model appear to result from a partial disruption of p53 function in which the concentration of the interfering protein must be neither too high (which results in a phenotype similar to that of the p53 knockout) nor too low (which results in a wild-type phenotype). Both groups have demonstrated that induction of p21Cip1, an important effector of p53-mediated growth arrest, is augmented in cells expressing truncated p53 proteins, and they suggest that accelerated aging phenotypes might in part be a reflection of accelerated senescence or loss of regenerative capacity of tissues secondary to a failure of cell proliferation.

What about Shc?

There is another indirect path that connects p53 with the Daf/IGF-1 pathway. As shown in Fig. 1, there is indirect evidence linking p53 activation--through p66shc--to the control of forkhead transcription factors. Cell culture studies show that p53 activation by oxidative stress leads to an increase in p66shc protein abundance, and that phosphorylation of Ser36 of p66shc is required downstream of p53 to mediate oxidant stress-induced apoptosis (26). Of particular interest, both p53 null cells and p66shc null cells are relatively resistant to oxidant-induced apoptosis, and both types of knockout cells have lower endogenous reactive oxygen species (ROS) production as compared to wild-type cells. One possible consequence of reduced ROS production is less damage to macromolecules, including DNA and protein, and thus a slower rate of aging. Evidence of reduced oxidative damage to DNA in p66shc and p53 null cells has been obtained (26), as has evidence of reduced protein oxidation in p66shc null mice in a model of atherogenesis (27) (see "Acing the Stress Test").



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Fig. 1. Oxidative stress and the p66-p53 pathway. The IGF-1/Daf pathway regulates life span in response to environmental cues. This regulation is dependent on the transcriptional activity of a forkhead transcription factor. Increased longevity is accompanied by resistance to stress, particularly oxidative stress, and involves the induction of genes encoding protective proteins such as small heat shock proteins, SOD, and catalase. Shc proteins (especially p52 and p46) are targets of several protein tyrosine kinases (see inset) and participate in mitogenic activation of cells via the Ras pathway. p66shc possesses a unique N-terminal domain that becomes phosphorylated (serine-36) when cells are exposed to oxidative stress. [Top left: Modular structure of p66shc showing sites of serine (S) and tyrosine (Y) residues that are phosphorylated]. In cultured cells, activated (phosphorylated at serine-36) p66 inhibits forkhead activity. One consequence of this inhibition may be increased cellular ROS as a result of reduced transcription of forkhead targets such as SOD and catalase, setting up an amplification loop resulting in higher ROS levels. The ability of p66 to transduce ROS-dependent signals depends (at least partially) on the presence of the tumor suppressor p53. Cells missing either p53 or p66 are relatively resistant to oxidative stress and have lower baseline ROS production (perhaps because of higher baseline forkhead transcriptional activity). ROS is both an activator of and a downstream effector of the p66-p53 pathway. Chronic exposure of cultured primary fibroblasts to sublethal oxidative stress results in a decrease in replicative potential (senescence) in a p53 dependent fashion. The role of p66 in ROS-induced senescence remains to be determined. At higher ROS levels, the outcome is cell death (apoptosis), in part mediated by p53-dependent induction of genes that increase cellular ROS production. Both p53 and p66 may participate in protein-protein interactions in mitochondria that initiate cell death. Truncated p53 proteins (p44 and the form encoded by the m allele) appear to augment the activity of wild-type p53. Accelerated aging observed in mice carrying these mutations may involve constitutive activation of the p66-p53 pathway. In the absence of an oxidant stress, the p66 pathway may lie dormant. In the presence of oxidants (perhaps found in cells with age-related mitochondrial dysfunction), p66 becomes phosphorylated, and in concert with p53 it can amplify cellular ROS production.

 
What remains obscure at present is how p66shc influences cellular ROS production. A potential explanation is provided by the intriguing finding that p66shc can affect the activity of the mammalian forkhead transcription factor FKHRL1 (FOXO3a) (17) in cells challenged with hydrogen peroxide. In the presence of wild-type p66, FOXO3a becomes phosphorylated when cells are exposed to peroxide, and relocates to the cytoplasm, rendering it incapable of promoting transcription. Preservation of the transcriptional activity of the forkhead factor DAF-16 is essential for expression of longevity phenotypes in C. elegans daf pathway mutants. By analogy, increased longevity of p66 null animals (and lower ROS production by p66 null cells) might result from relief of a tonic repressive effect of p66 on forkhead transcription factor activity, allowing increased expression of the genes encoding endogenous antioxidant proteins such as SOD2 and catalase, which are transcriptional targets of FKHRL1. Loss of p66 might also interrupt a feedback mechanism (Fig. 1) whereby increases in cellular ROS are amplified by p66-dependent inhibition of forkhead activity. To date, no data concerning forkhead activity/localization in p66shc knockout mice have been published.

Although the fog surrounding the mechanism of action of p66 has not yet lifted, a recent paper suggests that about 25% of cellular p66 localizes to mitochondria and associates with mitochondrial heat shock protein HSP-70 (28) (see "Lethal Leak"), an interaction that appears to fall apart upon exposure of cells to oxidant stress (Fig. 2). This observation raises a number of follow-up questions, some of which are self-contradictory: How does a fraction of p66 localize to mitochondria, and is this localization dependent on phosphorylation of the serine residue at position 36? If p66 and HSP-70 (plus other partners?) form an inert complex in mitochondria that becomes activated and dissociates upon oxidant stress, which component is responsible for downstream effects such as reduction in membrane potential? Remember that cells lacking p66 (and thus constitutively lacking such an inert complex) are oxidant stress-resistant and produce less ROS at baseline; does this mean that p66 is the active component? If so, one function of HSP-70 may be to hold p66 in an inactive conformation pending receipt of an activation signal triggered by increased ROS. Proposing that oxidative damage in some way releases p66 is tricky, because one might expect HSP-70 to bind more avidly to proteins that misfold upon oxidation. Perhaps equally likely, p66 might sequester a portion of HSP-70 and modify its functional activity in an as-yet-unidentified fashion. This would at least conform to the already well-documented role of HSP-70 in stress responses, including the response to oxidative stress and apoptosis. Modulation of HSP-70 expression in cultured cells via overexpression and via knockdown should help to choose between these divergent models.



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Fig. 2. Effects of p66shc on mitochondria. p66 might affect mitochondrial function both directly and indirectly. (A) It has been reported that a fraction of p66 (~25%) localizes to mitochondria. It is unclear whether the entire pool of p66 cycles into and out of mitochondria, or if a portion of p66 undergoes modification or interaction with a partner protein, facilitating localization to mitochondria. p66 localizing to mitochondria can be copurified with mitochondrial HSP-70 (mtHsp70), an interaction that falls apart when cells are exposed to oxidant. p66 in mitochondria may have a role in triggering mitochondrial permeability transition, but the mechanism whereby this might occur is not clear. (B) Direct and indirect effects: Through inhibition of forkhead transcription factor activity, p66 can impact mitochondrial ROS scavenging by suppressing transcription of antioxidant proteins such as SOD2. This intersection with the terminus of the Daf pathway might be the mechanism by which p66 affects life span. An alternate (but nonexclusive) hypothesis is that p66 functions within mitochondria to change sensitivity to apoptotic stimuli by altering the threshold for opening of a mitochondrial channel called the mitochondrial permeability transition pore (MPTP). In this way, p66 would have a role at the terminus of a p53-dependent death pathway in response to sufficiently strong oxidant stress. IMS, intermembrane space; mt{Delta}{Psi}, mitochondrial transmembrane potential.

 
Overexpression of p66 in murine or human fibroblasts has only a modest effect on oxidant sensitivity (causing it to be increased), whereas knockdown or knockout of p66 results in a more dramatic increase in oxidant resistance (29). These observations are consistent with the idea that oxidant stress sensitivity and resistance through p66 require only a fraction of the total cellular p66 and might involve interaction with another cellular component that is normally present in limited quantities, perhaps making HSP-70 an unlikely candidate, because it is an abundant protein. Although cultured fibroblasts express detectable p66 and can tolerate high concentrations of exogenous p66, little is known about normal expression of p66 in tissues. In our experience, although the p52 and p46 isoforms can readily be detected in (murine) tissue lysates, little or no p66 is present. Further, hematopoietic tissues and cell lines do not express p66, and the generation of stable clones expressing p66 is difficult, leading to the suggestion that transient expression of the protein may lead to down-regulation of immune responses by inducing (T lymphocyte) cell death (30). At a minimum, these observations suggest that tissues differ in their sensitivity to p66-dependent signals that result in cell death, presumably because they express different quantities of p66-interacting proteins. It will be interesting to see the effect of conditional knockout or knockdown of p66 in specific tissues to determine which tissues are critically important for regulation of life span by this protein. Similarly, overexpression of p66 in specific tissues (hematopoietic cells, for instance) will help to clarify the role of this protein in the regulation of cell turnover.


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Citation: F. M. Martin, J. S. Friedman, Ticking Fast or Ticking Slow, Through Shc Must You Go? Sci. Aging Knowl. Environ. 2004 (32), pe32 (2004).




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