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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Dean L, McEntyre J, editors. Coffee Break: Tutorials for NCBI Tools [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 1999-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/coffeebrk/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-coffeebrk-lrg.png" alt="Cover of Coffee Break" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Coffee Break: Tutorials for NCBI Tools [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK222181_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK222181_dtls__"><div>Dean L, McEntyre J, editors.</div><div>Bethesda (MD): <a href="https://www.ncbi.nlm.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Center for Biotechnology Information (US)</a>; 1999-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/coffeebrk/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/coffeebrk/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/coffeebrk/cb42_copper/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/coffeebrk/cb40LDL/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK222181_"><span class="title" itemprop="name">Yoda and the fountain of youth?</span></h1><div class="subtitle whole_rhythm">The many hats of IGF-1</div><p class="contrib-group"><span itemprop="author">Laura Dean</span>, MD.</p><a data-jig="ncbitoggler" href="#__NBK222181_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK222181_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Laura Dean</span>, MD<sup>1</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> NCBI<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.mln.ibcn@naed" class="oemail">vog.hin.mln.ibcn@naed</a></div></div></div><p class="small">Created: <span itemprop="datePublished">July 21, 2014</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><p>Insulin growth factor (IGF-1) is on the World Anti-Doping Agency list of banned
|
||
substances. In children, IGF-1 is important for growth, and in adults, it continues to
|
||
have anabolic effects. Although data are lacking for humans, animal studies have shown
|
||
that IGF-1 can increase muscle mass and speed up healing of injured tendons (<a class="bk_pop" href="#cb41Yoda.REF.1" data-bk-pop-others="cb41Yoda.REF.2">1, 2</a>).</p><p>IGF-1 also appears to play a part in the aging process. It has long been known that one
|
||
of the causes of short stature, or dwarfism, is a lack of the IGF-1 hormone in
|
||
childhood. And now it appears that IGF-1 deficiency also influences longevity.</p><p>The <i>C. elegans</i> worm can live for twice as long if it is genetically
|
||
engineered to have a mutation in <i>daf-2</i> (equivalent to
|
||
<i>IGF-1</i> receptor in humans) (<a class="bk_pop" href="#cb41Yoda.REF.3">3</a>). And Yoda, a dwarf mouse, lived twice as long as
|
||
normal laboratory mouse. With Princess Leia (his cage mate) for company, Yoda lived long
|
||
enough to celebrate his 4<sup>th</sup> birthday (<a class="bk_pop" href="#cb41Yoda.REF.1">1</a>).</p><p>
|
||
|
||
</p><div id="cb41Yoda.Fa" class="figure bk_fig"><div class="graphic"><img src="/books/NBK222181/bin/cb41Yoda-Image001.jpg" alt="Yoda, a Snell dwarf mouse (left), sniffing his cage-mate, Princess Leia (right)" /></div><div class="caption"><p>Yoda, a Snell dwarf mouse (left), sniffing his cage-mate, Princess Leia (right).
|
||
Dwarf mice are usually caged with normal-sized mice to help them to keep warm. <br />Photo credit: Richard Miller, University of Michigan Medical School</p></div></div><p>Dwarf mice, like the long-living worms, lack IGF-1. These mice are commonly used to study
|
||
the effects of aging and there are three main types. The Snell and Ames dwarf mice have
|
||
been bred to inherit mutations in <i>Pit-1</i> and <i>Prop1</i>
|
||
genes, respectively, which disrupt the embryonic development of the pituitary gland. As
|
||
a result, both types of mice lack multiple hormones, including growth hormone,
|
||
prolactin, and thyroid stimulating hormone.</p><p>The third type of dwarf mouse, the Laron dwarf, is a knock-out mouse model. This mouse
|
||
has a targeted gene deletion of either the growth hormone receptor (GHR-KO) or the
|
||
growth hormone binding protein (GHBP-KO). So even though this mouse produces growth
|
||
hormone, it is still growth-restricted because it is unable to respond to it (<a class="bk_pop" href="#cb41Yoda.REF.4">4</a>). </p><p>Dwarf mice all share non-detectable levels of IGF-1 because one of the main actions of
|
||
growth hormone is to stimulate the production of IGF-1. Interestingly, in addition to
|
||
their small size, these mice also have reduced glucose and insulin levels, a lower
|
||
incidence of tumors, and a longer average and maximum lifespan. In fact, their lifespan
|
||
is increased by about 40% (<a class="bk_pop" href="#cb41Yoda.REF.4" data-bk-pop-others="cb41Yoda.REF.5">4,
|
||
5</a>).</p><div class="figure"><div class="mp-outer"><div class="ncbimedia" id="_bk_plyr_cb41tutorial"><video preload="none" poster="/books/NBK222181/bin/cb41slide.jpg" height="360" width="428"><source src="/books/NBK222181/bin/cb41tutorial-pmcvs_normal.flv" type="video/flash"></source><source src="/books/NBK222181/bin/cb41tutorial-pmcvs_normal.mp4" type="video/mp4"></source><source src="/books/NBK222181/bin/cb41tutorial-pmcvs_normal.webm" type="video/webm"></source></video></div></div><div class="half_rhythm"><a href="/books/NBK222181/bin/cb41tutorial.mp4">Download</a> video file.<sup>(196M, mp4)</sup></div></div><p>Such mouse models are useful, but is there a similar link between IGF-1 deficiency and
|
||
long-life seen in humans? Individuals with Laron syndrome have been helping to provide
|
||
this answer. Laron syndrome, also known as primary growth hormone insufficiency, is
|
||
caused by a mutation in the growth hormone receptor gene. A variety of different
|
||
mutations have been identified, and most affect the extracellular region of the receptor
|
||
that contains the growth hormone binding site. Affected individuals are typically less
|
||
than 4 feet tall, but if they are given IGF-1 before puberty, they may grow taller
|
||
(<a class="bk_pop" href="#cb41Yoda.REF.6" data-bk-pop-others="cb41Yoda.REF.7">6, 7</a>). </p><p>In southern Ecuador, there is a village where more than 250 individuals are thought to
|
||
have Laron syndrome, and this community has been well-studied. The results have been
|
||
surprising. For example, Laron patients appear to be protected against developing
|
||
cancer, a disease that is associated with aging (<a class="bk_pop" href="#cb41Yoda.REF.8">8</a>). Unfortunately, this apparent protection by IGF-1
|
||
deficiency does not translate to a longer life span compared to the general population
|
||
(<a class="bk_pop" href="#cb41Yoda.REF.9">9</a>). One factor may be a higher
|
||
death rate from causes of death that are not related to age, such as trauma and
|
||
alcoholism (<a class="bk_pop" href="#cb41Yoda.REF.10">10</a>). </p><p>So, could targeting IGF-1 be a pathway to the elixir of youth? We know that a certain
|
||
level of GH and IGF-1 is required for the functioning of the heart and other organs, and
|
||
the level of these hormones declines with age. However, GH and IGF-1 are oncogenes, and
|
||
using IGF-1 as a treatment for individuals who do not have a genetic deficiency might
|
||
lead to unexpected and harmful outcomes (<a class="bk_pop" href="#cb41Yoda.REF.11">11</a>). </p><p>What is clear is that extending the life of any organism, from worm to human, is an
|
||
incredibly complex process, involving many pathways, and potentially many drug targets.
|
||
And although IGF-1 may be one of these targets, knowing how to use this treatment safely
|
||
and effectively remains a long way away.</p><div id="cb41Yoda.Acknowledgments"><h2 id="_cb41Yoda_Acknowledgments_">Acknowledgments</h2><p>The author would like to thank Zvi Laron, Professor Emeritus of Pediatric
|
||
Endocrinology, Tel Aviv University, for reviewing this summary.</p></div><div id="cb41Yoda.References"><h2 id="_cb41Yoda_References_">References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.1">Pobojewski, S. <em>World's
|
||
oldest mouse reaches milestone birthday</em>. The University Record
|
||
[Online ] May 1, 2014]; Available from: <a href="http://www.ur.umich.edu/0304/Apr19_04/26.shtml" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>.ur.umich.edu<wbr style="display:inline-block"></wbr>/0304/Apr19_04/26.shtml</a>.</div></dd><dt>2.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.2">Kurtz C.A., et al. Insulin-like growth factor I accelerates
|
||
functional recovery from Achilles tendon injury in a rat
|
||
model. <span><span class="ref-journal">Am J Sports
|
||
Med. </span>1999;<span class="ref-vol">27</span>(3):363–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10352775" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10352775</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.3">Chen D., et al. Germline signaling mediates the
|
||
synergistically prolonged longevity produced by double mutations in
|
||
daf-2 and rsks-1 in C. elegans. <span><span class="ref-journal">Cell
|
||
Rep. </span>2013;<span class="ref-vol">5</span>(6):1600–10.</span> [<a href="/pmc/articles/PMC3904953/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3904953</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24332851" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24332851</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.4">Bartke A., Brown-Borg H. Life extension in the dwarf
|
||
mouse. <span><span class="ref-journal">Curr Top Dev
|
||
Biol. </span>2004;<span class="ref-vol">63</span>:189–225.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15536017" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15536017</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.5">Flurkey K., et al. Lifespan extension and delayed immune and
|
||
collagen aging in mutant mice with defects in growth hormone
|
||
production. <span><span class="ref-journal">Proc Natl Acad Sci U S
|
||
A. </span>2001;<span class="ref-vol">98</span>(12):6736–41.</span> [<a href="/pmc/articles/PMC34422/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC34422</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11371619" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11371619</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.6">Savage M.O., et al. Endocrine assessment, molecular
|
||
characterization and treatment of growth hormone insensitivity
|
||
disorders. <span><span class="ref-journal">Nat Clin Pract Endocrinol
|
||
Metab. </span>2006;<span class="ref-vol">2</span>(7):395–407.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16932322" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16932322</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.7">Laron, Z., Kopchick, J.
|
||
(Eds.), <em>Laron Syndrome - From Man to Mouse. Lessons from Clinical
|
||
and Experimental Experience</em>. 2011: Springer.</div></dd><dt>8.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.8">Steuerman R., Shevah O., Laron Z. Congenital IGF1 deficiency tends to confer
|
||
protection against post-natal development of
|
||
malignancies. <span><span class="ref-journal">Eur J
|
||
Endocrinol. </span>2011;<span class="ref-vol">164</span>(4):485–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21292919" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21292919</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.9">Aguiar-Oliveira M.H., et al. Longevity in untreated congenital growth
|
||
hormone deficiency due to a homozygous mutation in the GHRH receptor
|
||
gene. <span><span class="ref-journal">J Clin Endocrinol
|
||
Metab. </span>2010;<span class="ref-vol">95</span>(2):714–21.</span> [<a href="/pmc/articles/PMC2840870/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2840870</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19965916" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19965916</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.10">Laron Z. The GH-IGF1 axis and longevity. The paradigm
|
||
of IGF1 deficiency. <span><span class="ref-journal">Hormones
|
||
(Athens). </span>2008;<span class="ref-vol">7</span>(1):24–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18359741" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18359741</span></a>]</div></dd><dt>11.</dt><dd><div class="bk_ref" id="cb41Yoda.REF.11">Werner, H., Attias-Geva, Z.,
|
||
Bentov, I., Sarfstein, R., Schayek, H., Weinstein, D., Bruchim, I.,
|
||
<em>Cancer Genes, Tumor Suppressors, and Regulation of IGF1-R Gene
|
||
Expression in Cancer</em>, in <em>Insulin-like Growth Factors
|
||
and Cancer: From Basic Biology to Therapeutics</em>, D.E. LeRoith,
|
||
Editor. 2012, Springer Science. p. p159-177.</div></dd></dl></div><div style="display:none"><div style="display:none" id="figcb41YodaFa"><img alt="Image cb41Yoda-Image001" src-large="/books/NBK222181/bin/cb41Yoda-Image001.jpg" /></div></div><div id="bk_toc_contnr"></div></div></div>
|
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK222181/?report=reader">PubReader</a></li><li><a href="/books/NBK222181/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK222181" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK222181" style="display:none" title="Cite this Page"><div class="bk_tt">Dean L. Yoda and the fountain of youth?The many hats of IGF-1. 2014 Jul 21. In: Dean L, McEntyre J, editors. 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