Studies in invertebrates have led to the identification of a number of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signalling pathways. Examples include the related tyrosine kinase receptors InR (Drosophila melanogaster) and DAF-2 (Caenorhabditis elegans) that are homologues of the mammalian insulin-like growth factor type 1 receptor (IGF-1R). To investigate whether IGF-1R also controls longevity in mammals, we inactivated the IGF-1R gene in mice (Igf1r). Here, using heterozygous knockout mice because null mutants are not viable, we report that Igf1r(+/-) mice live on average 26% longer than their wild-type littermates (P < 0.02). Female Igf1r(+/-) mice live 33% longer than wild-type females (P < 0.001), whereas the equivalent male mice show an increase in lifespan of 16%, which is not statistically significant. Long-lived Igf1r(+/-) mice do not develop dwarfism, their energy metabolism is normal, and their nutrient uptake, physical activity, fertility and reproduction are unaffected. The Igf1r(+/-) mice display greater resistance to oxidative stress, a known determinant of ageing. These results indicate that the IGF-1 receptor may be a central regulator of mammalian lifespan.

/pdf/igf-1-receptor-regulates-lifespan-and-resistance-to-2xb62wp6xh.pdf

IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice

The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.

/pdf/ink4a-arf-expression-is-a-biomarker-of-aging-3jr7zs2o2o.pdf

Ink4a/Arf expression is a biomarker of aging

http://mcb.berkeley.edu/courses/mcb240/Meyer/sdarticle(10).pdf

The plasticity of aging: insights from long-lived mutants.

Reduced signaling of insulin-like peptides increases the life-span of nematodes, flies, and rodents. In the nematode and the fly, secondary hormones downstream of insulin-like signaling appear to regulate aging. In mammals, the order in which the hormones act is unresolved because insulin, insulin-like growth factor-1, growth hormone, and thyroid hormones are interdependent. In all species examined to date, endocrine manipulations can slow aging without concurrent costs in reproduction, but with inevitable increases in stress resistance. Despite the similarities among mammals and invertebrates in insulin-like peptides and their signal cascade, more research is needed to determine whether these signals control aging in the same way in all the species by the same mechanism.

http://science.sciencemag.org/content/sci/299/5611/1346.full.pdf

The endocrine regulation of aging by insulin-like signals.

Metformin as a Tool to Target Aging.

Ames dwarf mice are mutant mice that live about 50% longer than their normal siblings1,2,3 because they carry a 'longevity' gene, Prop1df, and in some phenotypic respects they resemble normal mice whose lifespan has been extended by restricted food intake2,4,5. Here we investigate whether these factors influence lifespan by similar or independent mechanisms, by deliberately reducing the number of calories consumed by Ames dwarf mice. We show that calorie restriction confers a further lifespan increase in the dwarfs, indicating that the two factors may act through different pathways.

/pdf/extending-the-lifespan-of-long-lived-mice-26o6eh4jkh.pdf

Extending the lifespan of long-lived mice.

David J. Clancy et al. (“Dietary restriction in long-lived dwarf flies,” Brevia, 12 April, p. [319][1]) report that chico1 mutant fruit flies, which live longer than controls at typical food concentrations, have shorter life-spans when kept under food shortage conditions that lead to increased longevity of nonmutant flies. They conclude that the slowing of aging by the chico1 mutation and caloric restriction (CR) occurs by overlapping mechanisms, and they use their findings to question our interpretation of our recent results ([1][2]) showing that CR extends the life-span of long-lived Ames dwarf mice.

We agree with Clancy et al. that a formal proof of synergistic interaction requires dose-response studies and examination of interactive effects at half-maximal or maximal response levels and that there could well be overlap between the pathways that lead to life-span extension in CR mice and those that slow aging in dwarf mice; indeed, our paper included a list of features shared by normal CR mice and genetically long-lived mice. However, a strong case can also be made for differences between the two modes of life-span extension, including the contrast between the leanness of CR mice and the normal-to-obese physique of dwarf mice, opposite changes in spontaneous locomotor activity ([2][3]), differences in corticosterone levels and food consumption, and distinct differences ([3][4]) in gene expression profiles between dwarf and CR mice. Our paper added further evidence that CR and df/df mice differ in important ways, by showing that restricted dwarf mice live longer than either normal dwarf mice or controls restricted to levels that are typically found optimal and by pointing out that CR seemed to affect the slope of the survival curve, while the df/df genotype altered not slope but offset point. The fruit fly data show some food concentrations at which control flies are longer lived than chico1 mutants, presumably representing greater susceptibility of mutant flies to starvation. We have not assessed the question of whether dwarf mice might also be more starvation sensitive than normals at very low food levels, but our conclusion that the two models involve partially disparate mechanisms would not be shaken by such a finding.

We believe that the findings of Clancy et al. from the fly and our findings from the mouse are complementary rather than conflicting. Further pursuit of the molecular basis for life-span extension in both restricted and mutant models is likely to be very informative.

1. [↵][5]1. A. Bartke 2. et al.
 , Nature 414, 412 (2001).
 [OpenUrl][6][CrossRef][7][PubMed][8]

2. [↵][9]1. J. Mattison 2. et al.
 , J. Am. Aging Assoc. 23, 9 (2000).
 [OpenUrl][10][PubMed][11]

3. [↵][12]1. R. A. Miller 2. et al.
 , in preparation.
 

# Response {#article-title-2}

Bartke et al. make several interesting and important points. We agree that to demonstrate that two different interventions extend life-span by overlapping mechanisms, it is necessary to maximize life-span by one (as we did in Drosophila by dietary restriction) and then to show that addition of the second does not further extend life-span (as we showed for the chico1 mutation). This result indicates that the two interventions extend life-span through a final common pathway or mechanism. However, had we not first maximized life-span by dietary restriction, we might not have discovered this, because at more moderate levels of dietary restriction, chico1 extends life-span.

More generally, interaction studies of this type cannot be used to demonstrate that two interventions act through different pathways. To illustrate this point, suppose that we had seen a further extension of life-span by chico1 at the level of dietary restriction that maximizes life-span. This might have meant that the mechanisms of extension of life-span were different. However, it might also have meant that the downstream pathway(s) through which dietary restriction extends life-span had not been fully activated at the food level that maximized life-span, so that further activation and extension of life-span were still possible by the addition of chico1 .

We also agree that many of the phenotypes associated with the Ames mutation and caloric restriction in the mouse are different. However, these other phenotypes may not be causal in the extension of life-span; they are correlated traits that may be induced by the upstream intervention through routes independent of those producing the extension of life-span.

 [1]: /lookup/doi/10.1126/science.1069366
 [2]: #ref-1
 [3]: #ref-2
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 [5]: #xref-ref-1-1 "View reference 1 in text"
 [6]: {openurl}?query=rft.jtitle%253DNature%26rft.stitle%253DNature%26rft.aulast%253DBartke%26rft.auinit1%253DA.%26rft.volume%253D414%26rft.issue%253D6862%26rft.spage%253D412%26rft.epage%253D412%26rft.atitle%253DExtending%2Bthe%2Blifespan%2Bof%2Blong-lived%2Bmice.%26rft_id%253Dinfo%253Adoi%252F10.1038%252F35106646%26rft_id%253Dinfo%253Apmid%252F11719795%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
 [7]: /lookup/external-ref?access_num=10.1038/35106646&link_type=DOI
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 [9]: #xref-ref-2-1 "View reference 2 in text"
 [10]: {openurl}?query=rft.jtitle%253DJ.%2BAm.%2BAging%2BAssoc.%26rft.volume%253D23%26rft.spage%253D9%26rft_id%253Dinfo%253Apmid%252F23604794%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
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 [12]: #xref-ref-3-1 "View reference 3 in text"

Dietary restriction and life-span.

Soft contact lenses (SCLs) have recently been introduced as an alternative method for human tear protein sampling. However, SCLs are available in a variety of chemical compositions which affect protein binding specificity. Here we analyzed 8 different SCL materials to identify an optimal lens for tear protein sampling. Polymer contamination, mass spectrometry (MS) sample preparation method, total protein capture, individual protein specificity, and SCL cost were all assessed. Using a filter-aided sample prep (FASP) method with 4M guanidine for protein removal, only etafilcon A and verofilcon A did not have significant polymer contamination. Polymer was successfully removed using phosphate buffered saline (PBS) with S-Trap columns for all SCL materials, though yielding a slightly lower number of protein identifications per sample. Minor quantitative differences were observed between SCL materials. However, we also saw significant intersubject variation in protein abundance. Of all the assessed SCL materials, verofilcon A lenses yielded the most total protein while comfilcon A and senofilcon A had the least protein variability. As a newly released daily disposable modality (Precision 1, Alcon), verofilcon A has one of the longest predictable production schedules and one of the lowest costs per lens, making it beneficial for large-scale experiments and diagnostics. Furthermore, we demonstrate how protein binding bias with SCL tear sampling is useful for intra-experiment normalization. Overall, these experiments have led us to optimize our previous protocol for SCL tear protein sampling, highlighting important differences between SCL materials and identifying etafilcon A and verofilcon A as optimal materials for tear protein sampling.

/pdf/proteomic-specificity-of-soft-contact-lenses-for-tear-3gyoa54a.pdf

Proteomic Specificity of Soft Contact Lenses for Tear Protein Sampling

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Extending the lifespan of long-lived mice.

Dietary restriction and life-span.

Proteomic Specificity of Soft Contact Lenses for Tear Protein Sampling