The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an insulin/insulin-like growth factor (IGF) signaling pathway. In the nematode Caenorhabditis elegans , insulin/IGF signaling regulates adult longevity. We found that mutation of chico extends fruit fly median life-span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life-span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life-span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved.

Caloric restriction (CR) protects against aging and disease but the mechanisms by which this affects mammalian lifespan are unclear. We show in mice that deletion of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway component ribosomal S6 protein kinase 1 (S6K1) led to increased lifespan and resistance to age-related pathologies such as bone, immune and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian lifespan, and suggest therapeutic manipulation of S6K1 and AMPK might mimic CR and provide broad protection against diseases of aging. Genetic studies in S. cerevisiae, C. elegans and D. melanogaster implicate several mechanisms in the regulation of lifespan. These include the insulin and insulin-like growth factor 1 (IGF-1) signaling (IIS) and mammalian target of rapamycin (mTOR) pathways which both activate the downstream effector ribosomal protein S6 kinase 1 (S6K1) (1, 2). Although the role of these pathways in mammalian aging is less clear, there is mounting evidence that IIS regulates lifespan in mice (1). Global deletion of one allele of the IGF1 receptor (Igf1r), adipose-specific deletion of the insulin receptor (Insr), global deletion of insulin receptor substrate protein 1 (Irs1) or neuron-specific deletion of Irs2 all increase mouse lifespan (1). Lifespan-extending mutations in the somatotropic axis also appear to work through attenuated IIS (3). Igf1r has also been implicated as a modulator of human longevity (4). However, the action of downstream effectors of IIS or mTOR signaling in mammalian longevity is not fully understood.S6K1 transduces anabolic signals that indicate nutritional status to regulate cell size and growth and metabolism through various mechanisms (5). These include effects on the translational machinery and on cellular energy levels through the activity of adenosine monophosphate (AMP)-activated protein kinase (AMPK) (6, 7). Furthermore, S6K1 serine phosphorylates IRS1 and IRS2 thereby decreasing insulin signaling (5). Given the key role of S6K1 in IIS and mTOR signaling, and the regulation of aging in lower organisms by mTOR, S6K, and their downstream effectors (2) we used log rank testing to evaluate differences in lifespan of wild-type (WT) and S6K1 -/-littermate mice on a C57BL/6 background (8). Data for both sexes combined showed median lifespan in S6K1 -/-mice increased by 80 days (from 862 to 942 days) or 9% relative to that of WT mice (X 2 = 10.52, p < 0.001) ( Fig. 1A and Table 1). Maximum lifespan (mean lifespan of the oldest 10% within a cohort) was also increased (1077±16 and 1175±24 days, p < 0.01 for WT and S6K1 -/-mice, respectively). Analysis of each sex separately showed that median lifespan in female S6K1 -/-mice was increased, by 153 d...

SummaryThe biguanide drug metformin is widely prescribed to treat type 2 diabetes and metabolic syndrome, but its mode of action remains uncertain. Metformin also increases lifespan in Caenorhabditis elegans cocultured with Escherichia coli. This bacterium exerts complex nutritional and pathogenic effects on its nematode predator/host that impact health and aging. We report that metformin increases lifespan by altering microbial folate and methionine metabolism. Alterations in metformin-induced longevity by mutation of worm methionine synthase (metr-1) and S-adenosylmethionine synthase (sams-1) imply metformin-induced methionine restriction in the host, consistent with action of this drug as a dietary restriction mimetic. Metformin increases or decreases worm lifespan, depending on E. coli strain metformin sensitivity and glucose concentration. In mammals, the intestinal microbiome influences host metabolism, including development of metabolic disease. Thus, metformin-induced alteration of microbial metabolism could contribute to therapeutic efficacy—and also to its side effects, which include folate deficiency and gastrointestinal upset.PaperClip

Reactive oxygen species are not only harmful agents that cause oxidative damage in pathologies, they also have important roles as regulatory agents in a range of biological phenomena. The relatively recent development of this more nuanced view presents a challenge to the biomedical research community on how best to assess the significance of reactive oxygen species and oxidative damage in biological systems. Considerable progress is being made in addressing these issues, and here we survey some recent developments for those contemplating research in this area.

Recent evidence suggests that alterations in insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, in several mouse mutants, impairment of the growth hormone (GH)/IGF1 axis increases life span and also insulin sensitivity. However, the intracellular signaling route to altered mammalian aging remains unclear. We therefore measured the life span of mice lacking either insulin receptor substrate (IRS) 1 or 2, the major intracellular effectors of the IIS receptors. Our provisional results indicate that female Irs1-/- mice are long-lived. Furthermore, they displayed resistance to a range of age-sensitive markers of aging including skin, bone, immune, and motor dysfunction. These improvements in health were seen despite mild, lifelong insulin resistance. Thus, enhanced insulin sensitivity is not a prerequisite for IIS mutant longevity. Irs1-/- female mice also displayed normal anterior pituitary function, distinguishing them from long-lived somatotrophic axis mutants. In contrast, Irs2-/- mice were short-lived, whereas Irs1+/- and Irs2+/- mice of both sexes showed normal life spans. Our results therefore suggest that IRS1 signaling is an evolutionarily conserved pathway regulating mammalian life span and may be a point of intervention for therapies with the potential to delay age-related processes.

Over-expression of sirtuins (NAD+-dependent protein deacetylases) has been reported to increase lifespan in budding yeast, Caenorhabditis elegans and Drosophila melanogaster1-3. Studies of gene effects on ageing are vulnerable to confounding effects of genetic background4. We re-examined the reported effects of sirtuin over-expression on ageing and found that standardisation of genetic background and use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high level sir-2.1 over-expression1 abrogated the longevity increase, but not sir-2.1 over-expression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low copy number sir-2.1 over-expression2 also abrogated longevity. A Drosophila strain with ubiquitous over-expression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported3, but not relative to the appropriate transgenic controls, and nor was a new line with stronger over-expression of dSir2. These findings underscore the importance of controlling for genetic background and the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life extending effect of dietary restriction (DR) on ageing in Drosophila has also been reported to be dSir2 dependent3. We found that DR increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects on lifespan in C. elegans and Drosophila.

Discovering the biological basis of aging is one of the greatest remaining challenges for science. Work on the biology of aging has discovered a range of interventions and pathways that control aging rate. A picture is emerging of a signaling network that is sensitive to nutritional status and that controls growth, stress resistance, and aging. This network includes the insulin/IGF-1 and target of rapamycin (TOR) pathways and likely mediates the effects of dietary restriction on aging. Yet the biological processes upon which these pathways act to control life span remain unclear. A long-standing guiding assumption about aging is that it is caused by wear and tear, particularly damage at the molecular level. One view is that reactive oxygen species (ROS), including free radicals, generated as by-products of cellular metabolism, are a major contributor to this damage. Yet many recent tests of the oxidative damage theory have come up negative. Such tests have opened an exciting new phase in biogerontology in which fundamental assumptions about aging are being reexamined and revolutionary concepts are emerging. Among these concepts is the hyperfunction theory, which postulates that processes contributing to growth and reproduction run on in later life, leading to hypertrophic and hyperplastic pathologies. Here we reexamine central concepts about the nature of aging.

The superoxide radical (O 2 − ) has long been considered a major cause of aging. O 2 − in cytosolic, extracellular, and mitochondrial pools is detoxified by dedicated superoxide dismutase (SOD) isoforms. We tested the impact of each SOD isoform in Caenorhabditis elegans by manipulating its five sod genes and saw no major effects on life span. sod genes are not required for daf-2 insulin/ IGF-1 receptor mutant longevity. However, loss of the extracellular Cu/ZnSOD sod-4 enhances daf-2 longevity and constitutive diapause, suggesting a signaling role for sod-4. Overall, these findings imply that O 2 − is not a major determinant of aging in C. elegans.Supplemental material is available at http://www.genesdev.org.Received April 11, 2008; revised version accepted September 29, 2008. Many forms of pathology lead to elevated levels of damage to biological macromolecules (Halliwell and Gutteridge 2007). This is also true of aging, the poorly understood biological process that leads to progressive deterioration and death. One strategy to discover the underlying mechanisms of aging has been to seek the causes of its associated molecular damage. An important early theory, proposed by Harman (1956), postulates that the cause might be oxygen free radicals. Harman later developed the theory, proposing a central role for the superoxide (O 2 − ) radical, issuing from the mitochondrial electron transport chain (Harman 1972). During the last few decades, much effort has been invested in tests of this nexus of theories (for review, see Muller et al. 2007 (Fujii et al. 1998). Two mitochondrial MnSOD isoforms are encoded by sod-2 and sod-3 (Giglio et al. 1994;Suzuki et al. 1996;Hunter et al. 1997).This superabundance of SOD isoforms has been a technical hurdle to investigations of the role of SOD and O 2 − in aging in C. elegans, and some of the sod genes have been barely studied. In situ gel SOD activity assays of a sod-1 deletion mutant imply that this gene encodes the major cytosolic Cu/ZnSOD (Jensen and Culotta 2005), leaving the function of sod-5 unclear. sod-3 mRNA levels are elevated in the dauer larva (Honda and Honda 1999), suggesting that this gene may play a special role in antioxidant defense in this long-lived, stress-resistant diapausal stage, but the role of sod-2 has remained obscure. In this study, we describe in detail the function of each of the five sod genes, characterizing their expression, and the phenotypic effects of manipulating their expression. This has allowed us to assess the effect on life history, especially aging, of each of the three major O 2 − pools, thereby critically testing the role of SOD and, by inference, O 2 − , in longevity assurance and aging. O 2 − can affect living organisms in a variety of ways. It can cause molecular damage that might contribute to aging; thus, one expectation of our study was that lowering SOD activity and increasing O 2 − levels might accelerate aging, and vice versa. H 2 O 2 derived from O 2 − can also act a secondary messenger-for example, in receptor tyrosine ...