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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Aging</journal-id>
<journal-title>Frontiers in Aging</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Aging</abbrev-journal-title>
<issn pub-type="epub">2673-6217</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="publisher-id">1380016</article-id>
<article-id pub-id-type="doi">10.3389/fragi.2024.1380016</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Aging</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Decoding lifespan secrets: the role of the gonad in <italic>Caenorhabditis elegans</italic> aging</article-title>
<alt-title alt-title-type="left-running-head">Pires da Silva et al.</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fragi.2024.1380016">10.3389/fragi.2024.1380016</ext-link>
</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Pires da Silva</surname>
<given-names>Andre</given-names>
</name>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
<uri xlink:href="https://loop.frontiersin.org/people/142743/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/supervision/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kelleher</surname>
<given-names>Rhianne</given-names>
</name>
<uri xlink:href="https://loop.frontiersin.org/people/2651889/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
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<contrib contrib-type="author">
<name>
<surname>Reynoldson</surname>
<given-names>Luke</given-names>
</name>
<uri xlink:href="https://loop.frontiersin.org/people/2646051/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
</contrib>
</contrib-group>
<aff>
<institution>School of Life Sciences</institution>, <institution>University of Warwick</institution>, <addr-line>Coventry</addr-line>, <country>United Kingdom</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/37407/overview">John Tower</ext-link>, University of Southern California, United States</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/153530/overview">Arnab Mukhopadhyay</ext-link>, National Institute of Immunology (NII), India</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/984050/overview">Ilke Sen</ext-link>, INSERM U955 Institut Mondor de Recherche Biom&#xe9;dicale (IMRB), France</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Andre Pires da Silva, <email>andre.pires@warwick.ac.uk</email>
</corresp>
</author-notes>
<pub-date pub-type="epub">
<day>26</day>
<month>03</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>5</volume>
<elocation-id>1380016</elocation-id>
<history>
<date date-type="received">
<day>31</day>
<month>01</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>18</day>
<month>03</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Pires da Silva, Kelleher and Reynoldson.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Pires da Silva, Kelleher and Reynoldson</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>The gonad has become a central organ for understanding aging in <italic>C. elegans</italic>, as removing the proliferating stem cells in the germline results in significant lifespan extension. Similarly, when starvation in late larval stages leads to the quiescence of germline stem cells the adult nematode enters reproductive diapause, associated with an extended lifespan. This review summarizes recent advancements in identifying the mechanisms behind gonad-mediated lifespan extension, including comparisons with other nematodes and the role of lipid signaling and transcriptional changes. Given that the gonad also mediates lifespan regulation in other invertebrates and vertebrates, elucidating the underlying mechanisms may help to gain new insights into the mechanisms and evolution of aging.</p>
</abstract>
<kwd-group>
<kwd>diapause</kwd>
<kwd>evolution of aging</kwd>
<kwd>lipids</kwd>
<kwd>germline</kwd>
<kwd>reproduction</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Genetics, Genomics and Epigenomics of Aging</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>Introduction</title>
<p>Aging, characterized by a time-dependent deterioration of physiological function, is a phenomenon that is almost universally observed in biology (<xref ref-type="bibr" rid="B74">Jones et al., 2014</xref>). Pioneering work using the nematode <italic>C. elegans</italic> has provided insights into the genetics of aging (<xref ref-type="bibr" rid="B88">Klass, 1977</xref>; <xref ref-type="bibr" rid="B73">Johnson and Wood, 1982</xref>; <xref ref-type="bibr" rid="B89">Klass, 1983</xref>; <xref ref-type="bibr" rid="B44">Friedman and Johnson, 1988</xref>). These studies showed that single gene mutations can greatly extend <italic>C. elegans</italic> lifespan, sometimes up to tenfold compared to its normal lifespan (<xref ref-type="bibr" rid="B44">Friedman and Johnson, 1988</xref>; <xref ref-type="bibr" rid="B78">Kenyon et al., 1993</xref>; <xref ref-type="bibr" rid="B13">Ayyadevara et al., 2008</xref>). Several pathways, including the highly conserved insulin signaling pathway and a germline signaling pathway (<xref ref-type="bibr" rid="B77">Kenyon, 2011</xref>; <xref ref-type="bibr" rid="B56">Ghazi, 2013</xref>), are involved in modulating aging (<xref ref-type="bibr" rid="B152">Soo et al., 2023</xref>).</p>
<p>Compared to the insulin signaling pathway, the germline signaling pathway is relatively understudied (<xref ref-type="bibr" rid="B101">Lemieux and Ashrafi, 2016</xref>). The initial discovery was based on removing germline precursor cells in <italic>C. elegans</italic> larvae (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>). These laser-ablated nematodes, which have an intact somatic gonad without germline cells, reach adulthood and live substantially longer than non-ablated animals (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>). These findings initially supported a theory of aging stating that energy resources could be diverted from reproduction to somatic maintenance to extend lifespan [reviewed in (<xref ref-type="bibr" rid="B86">Kirkwood, 1991</xref>; <xref ref-type="bibr" rid="B100">Lemaitre et al., 2015</xref>)]. However, the complete removal of the reproductive system (both the somatic gonad and the germline) does not extend lifespan, contradicting this &#x201c;resource allocating&#x201d; theory of aging (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>). These ablation experiments suggest that whereas somatic gonad signals may lengthen lifespan, they are counteracted by lifespan-shortening germline signals (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>).</p>
<p>Mutants that genetically mimic laser-ablated animals have been used to study the regulation of lifespan extension in germline-less animals. The use of such mutants allows the generation of a large number of animals lacking a germline. Biochemical analysis of germlineless mutants indicates they are rich in triglyceride/phospholipid content (<xref ref-type="bibr" rid="B126">O&#x2019;Rourke et al., 2009</xref>), suggesting that the lifespan extension of germlineless worms may involve changes to fat metabolism.</p>
<p>Naturally, in the wild, there are no animals lacking germline. Therefore, it is crucial to determine if the conditions that prevent germline proliferation (e.g., starvation) and lead to extended lifespan involve the same regulatory pathways as those observed in lab-engineered germline-less animals. These studies will give insights into aging mechanisms and theories of aging alike. This review aims to address the mechanisms behind the increased lifespan of mutants lacking proliferating germ cells, connecting these findings with recent theories of aging, identifying gaps in the literature, and suggesting potential future research directions.</p>
</sec>
<sec id="s2">
<title>Senescent pathologies in aging <italic>C. elegans</italic>
</title>
<p>
<italic>C. elegans</italic> is usually maintained in genetically homogenous populations of self-fertilizing hermaphrodites. They propagate on agar plates, using the bacterium <italic>Escherichia coli</italic> as a food source (<xref ref-type="bibr" rid="B158">Stiernagle, 2006</xref>). In these conditions, the hermaphrodite lives for an average of 18&#xa0;days at 20&#xb0;C. In its natural habitat on decaying vegetable matter, <italic>C. elegans</italic> feeds on uncharacterized bacterial and unicellular eukaryotes (<xref ref-type="bibr" rid="B40">F&#xe9;lix and Duveau, 2012</xref>; <xref ref-type="bibr" rid="B43">Fr&#xe9;zal and F&#xe9;lix, 2015</xref>). Although <italic>C. elegans</italic> lifespan has been determined in complex environments (<xref ref-type="bibr" rid="B168">Van Voorhies et al., 2005</xref>), its lifespan in the original habitat and native food is not known. Additionally, it is unclear if <italic>C. elegans</italic> displays signs of senescence in its natural environment (<xref ref-type="bibr" rid="B123">Nussey et al., 2013</xref>).</p>
<p>In the laboratory, the aging <italic>C. elegans</italic> hermaphrodite displays multiple pathologies, including the degeneration of the germline, pharynx, body wall muscle, vulva and intestine (<xref ref-type="bibr" rid="B47">Garigan et al., 2002</xref>; <xref ref-type="bibr" rid="B65">Herndon et al., 2002</xref>; <xref ref-type="bibr" rid="B116">McGee et al., 2011</xref>; <xref ref-type="bibr" rid="B35">de la Guardia et al., 2016</xref>; <xref ref-type="bibr" rid="B99">Leiser et al., 2016</xref>), ectopic deposition of lipids (<xref ref-type="bibr" rid="B128">Palikaras et al., 2017</xref>; <xref ref-type="bibr" rid="B129">Palikaras et al., 2023</xref>) and yolk (lipoproteins) (<xref ref-type="bibr" rid="B39">Ezcurra et al., 2018</xref>; <xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>; <xref ref-type="bibr" rid="B155">Spanoudakis and Tavernarakis, 2023</xref>). These pathologies start relatively early, with some already apparent on only the third day of adulthood (<xref ref-type="bibr" rid="B65">Herndon et al., 2002</xref>; <xref ref-type="bibr" rid="B39">Ezcurra et al., 2018</xref>). Additionally, measures of health, such as vigor of movement, effective pharyngeal pumping, and resistance to stressors (including oxidative stress or thermotolerance), decline with age in <italic>C. elegans</italic> (<xref ref-type="bibr" rid="B14">Bansal et al., 2015</xref>). It must be noted, however, that measures of health in <italic>C. elegans</italic> have not yet been strictly defined (<xref ref-type="bibr" rid="B14">Bansal et al., 2015</xref>).</p>
<p>
<italic>C. elegans</italic> males tend to live longer than hermaphrodites, provided they are kept in isolation (<xref ref-type="bibr" rid="B115">McCulloch and Gems, 2003</xref>; <xref ref-type="bibr" rid="B6">Ancell and Pires-daSilva, 2017</xref>). Because male proportions are low in the laboratory and nature (<xref ref-type="bibr" rid="B43">Fr&#xe9;zal and F&#xe9;lix, 2015</xref>), combined with their tendency to kill each other when raised in groups, and their propensity to escape the plates, determination of their lifespan is often excluded (<xref ref-type="bibr" rid="B53">Gems and Riddle, 2000</xref>). In a few studies designed to characterize the pathological changes in aging males, neither intestine (<xref ref-type="bibr" rid="B39">Ezcurra et al., 2018</xref>) nor germline disintegration occurs (<xref ref-type="bibr" rid="B35">de la Guardia et al., 2016</xref>), and motor decline is detected before any visible morphological changes (<xref ref-type="bibr" rid="B61">Guo et al., 2012</xref>).</p>
</sec>
<sec id="s3">
<title>Comparing germline-ablated animals and germline-less mutants</title>
<p>The first larval stage of <italic>C. elegans</italic> contains two germline precursor cells, named Z2 and Z3 (<xref ref-type="bibr" rid="B82">Kimble and Hirsh, 1979</xref>). Removal of these cells by laser cell ablation results in an adult with an intact somatic gonad lacking oocytes and sperm. <italic>C. elegans</italic> hermaphrodites lacking a proliferating germline are long-lived (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>) and resistant to stress (<xref ref-type="bibr" rid="B10">Arantes-Oliveira et al., 2002</xref>; <xref ref-type="bibr" rid="B151">Sinha and Rae, 2014</xref>). In <italic>C. elegans</italic> males, the ablation of germline precursor cells results in a slight life extension when grown on agar plates (<xref ref-type="bibr" rid="B10">Arantes-Oliveira et al., 2002</xref>), but not when kept in liquid culture (<xref ref-type="bibr" rid="B114">McCulloch, 2003</xref>).</p>
<p>In the wild-type <italic>C. elegans</italic> adult, the proliferation of the germline stem cells is mediated by signals from the distal tip cells of the somatic gonad [for review, see (<xref ref-type="bibr" rid="B69">Hubbard and Schedl, 2019</xref>)]. Removing these somatic cells causes premature differentiation of the germline stem cells into gametes (<xref ref-type="bibr" rid="B84">Kimble and White, 1981</xref>). <italic>glp-1</italic>, a member of the Notch receptor family (<xref ref-type="bibr" rid="B179">Yochem et al., 1988</xref>; <xref ref-type="bibr" rid="B12">Austin and Kimble, 1989</xref>; <xref ref-type="bibr" rid="B83">Kimble and Simpson, 1997</xref>) expressed in the germline (<xref ref-type="bibr" rid="B28">Cinquin et al., 2015</xref>; <xref ref-type="bibr" rid="B62">Gutnik et al., 2018</xref>; <xref ref-type="bibr" rid="B153">Sorensen et al., 2020</xref>), is required to keep stem cells in an undifferentiated state. Thus, <italic>glp-1</italic> loss-of-function mutants mimic the Z2/Z3-ablated animals because both lack proliferating and undifferentiated germ cells. The most commonly used mutants are temperature-sensitive and are subjected to the restrictive temperature during larval stages to induce their phenotype (<xref ref-type="bibr" rid="B10">Arantes-Oliveira et al., 2002</xref>). Similar to the Z2/Z3-ablated animals, <italic>glp-1</italic> mutant hermaphrodites are long-lived (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>), display delayed senescent phenotypes (<xref ref-type="bibr" rid="B128">Palikaras et al., 2017</xref>) and are stress-resistant (<xref ref-type="bibr" rid="B10">Arantes-Oliveira et al., 2002</xref>; <xref ref-type="bibr" rid="B118">Miyata et al., 2008</xref>; <xref ref-type="bibr" rid="B2">Alper et al., 2010</xref>; <xref ref-type="bibr" rid="B152">Soo et al., 2023</xref>).</p>
<p>Additional examples of long-lived mutants with no proliferating germ cells include <italic>glp-4</italic>, <italic>mes-1,</italic> and <italic>pgl-1</italic> (<xref ref-type="bibr" rid="B19">Beanan and Strome, 1992</xref>; <xref ref-type="bibr" rid="B10">Arantes-Oliveira et al., 2002</xref>; <xref ref-type="bibr" rid="B161">Tatar, 2002</xref>; <xref ref-type="bibr" rid="B34">Curran et al., 2009</xref>). There are only a few studies with the <italic>pgl-1</italic> mutant; therefore, we will not discuss them further. <italic>glp-4</italic> codes for a tRNA synthetase (<xref ref-type="bibr" rid="B141">Rastogi et al., 2015</xref>). Similar to <italic>glp-1</italic> mutant animals, mutants for a loss-of-function temperature-sensitive allele of the gene <italic>glp-4</italic> (allele <italic>bn2</italic>) share many phenotypes: the germline does not proliferate (<xref ref-type="bibr" rid="B19">Beanan and Strome, 1992</xref>), fat storage is altered (<xref ref-type="bibr" rid="B173">Wang et al., 2008</xref>) and are resistant to stress (<xref ref-type="bibr" rid="B2">Alper et al., 2010</xref>; <xref ref-type="bibr" rid="B60">Greer et al., 2010</xref>; <xref ref-type="bibr" rid="B162">TeKippe and Aballay, 2010</xref>; <xref ref-type="bibr" rid="B93">Labbadia and Morimoto, 2015</xref>). <italic>glp-4</italic> (<italic>bn2)</italic> animals show delays to pathological signs of senescence (<xref ref-type="bibr" rid="B39">Ezcurra et al., 2018</xref>; <xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>) and have an extended lifespan (<xref ref-type="bibr" rid="B10">Arantes-Oliveira et al., 2002</xref>; <xref ref-type="bibr" rid="B125">Okuyama et al., 2010</xref>; <xref ref-type="bibr" rid="B162">TeKippe and Aballay, 2010</xref>), although there are reports that contradict this finding (<xref ref-type="bibr" rid="B165">Tohyama et al., 2008</xref>; <xref ref-type="bibr" rid="B60">Greer et al., 2010</xref>). For instance, <italic>glp-4</italic> animals have a wild-type lifespan when grown on live bacteria but show an extended lifespan only when grown on dead <italic>E. coli</italic> (<xref ref-type="bibr" rid="B162">TeKippe and Aballay, 2010</xref>).</p>
<p>When raised at the restrictive temperature, <italic>C. elegans</italic> mutants with the temperature-sensitive alleles of <italic>mes-1</italic> do not develop the germline precursors Z2 and Z3 and therefore do not contain germline cells (<xref ref-type="bibr" rid="B159">Strome et al., 1995</xref>). Lifespan extension and stress resistance were reported for both hermaphrodites (<xref ref-type="bibr" rid="B10">Arantes-Oliveira et al., 2002</xref>; <xref ref-type="bibr" rid="B2">Alper et al., 2010</xref>; <xref ref-type="bibr" rid="B177">Wu et al., 2015</xref>) and males, although only slightly for the latter (<xref ref-type="bibr" rid="B114">McCulloch, 2003</xref>).</p>
<p>The use of genetic mutations to replicate germline ablations has significantly advanced our understanding of the metabolic and genetic changes in animals lacking a proliferating germline (<xref ref-type="bibr" rid="B135">Pu et al., 2017</xref>; <xref ref-type="bibr" rid="B170">Wan et al., 2017</xref>; <xref ref-type="bibr" rid="B24">Burkhardt et al., 2023</xref>; <xref ref-type="bibr" rid="B26">Chaturbedi and Lee, 2023</xref>). However, the strengths of using <italic>glp-1</italic> temperature-sensitive alleles, such as <italic>glp-1</italic> (<italic>q224ts</italic>) and <italic>glp-1</italic> (<italic>bn18</italic>) (<xref ref-type="bibr" rid="B11">Austin and Kimble, 1987</xref>; <xref ref-type="bibr" rid="B90">Kodoyianni et al., 1992</xref>) may affect the interpretation of some studies as they show phenotypes in other tissues that could influence lifespan (<xref ref-type="bibr" rid="B9">Apfeld and Kenyon, 1999</xref>; <xref ref-type="bibr" rid="B150">Singh et al., 2011</xref>; <xref ref-type="bibr" rid="B37">Entchev et al., 2015</xref>; <xref ref-type="bibr" rid="B180">Zhang et al., 2018</xref>; <xref ref-type="bibr" rid="B166">Uno et al., 2021</xref>). Furthermore, the <italic>glp-4</italic> (<italic>bn2</italic>) mutant has a partial loss of function in the soma (<xref ref-type="bibr" rid="B141">Rastogi et al., 2015</xref>). Given that <italic>glp-4</italic> (<italic>bn2</italic>) does not show the same extent of lifespan extension as <italic>glp-1</italic> (<xref ref-type="bibr" rid="B162">TeKippe and Aballay, 2010</xref>), it would be beneficial to also include alternative models such as <italic>mes-1</italic> and <italic>pgl-1</italic>, or engineer new strains that allow spatiotemporal control of gene expression of genes that affect the proliferation of germline cells [e.g., (<xref ref-type="bibr" rid="B181">Zhang et al., 2015</xref>)].</p>
</sec>
<sec id="s4">
<title>Changes in transcriptional control mechanisms following germline removal</title>
<p>The germline removal in <italic>C. elegans</italic> results in the differential expression of thousands of transcripts (<xref ref-type="bibr" rid="B151">Sinha and Rae, 2014</xref>; <xref ref-type="bibr" rid="B21">Blackwell et al., 2015</xref>) and hundreds of proteins (<xref ref-type="bibr" rid="B92">Krijgsveld et al., 2003</xref>; <xref ref-type="bibr" rid="B15">Bantscheff et al., 2004</xref>; <xref ref-type="bibr" rid="B135">Pu et al., 2017</xref>). Among these are transcriptional regulators previously implicated in modulating lifespan, such as the pro-longevity transcription factors DAF-16 (mammalian FOXO) and DAF-12. The activity of DAF-16 is essential for the increased lifespan of animals with Z2/Z3 ablation (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>). The translocation of DAF-16 from the cytoplasm to the nucleus, a requirement for its function (<xref ref-type="bibr" rid="B104">Lin et al., 2001</xref>), relies on the activity of DAF-12. Interestingly, this specific activity of DAF-12 in regulating DAF-16 nuclear localization occurs only when the germline cells are removed (<xref ref-type="bibr" rid="B20">Berman and Kenyon, 2006</xref>). Similarly, the kinase MBK-1, the transcription elongation factor TCER-1, and the cytoskeleton adaptor protein KRI-1 modulate DAF-16 activity only in <italic>glp-1</italic> mutants, but not in long-lived mutants of the insulin pathway (<xref ref-type="bibr" rid="B20">Berman and Kenyon, 2006</xref>; <xref ref-type="bibr" rid="B110">Mack et al., 2017</xref>; <xref ref-type="bibr" rid="B4">Amrit et al., 2019</xref>).</p>
<p>DAF-12 is a nuclear hormone receptor similar to the vitamin D receptors found in vertebrates (<xref ref-type="bibr" rid="B8">Antebi et al., 2000</xref>). Its activation is mediated by the ligand dafachronic acid (DA), a cholesterol-derived hormone (<xref ref-type="bibr" rid="B120">Motola et al., 2006</xref>). However, significant lifespan extension can be induced in animals lacking germline and somatic reproductive tissues by supplementation with DA (<xref ref-type="bibr" rid="B178">Yamawaki et al., 2010</xref>). This suggests that the somatic gonad triggers the production of the DAF-12 ligand in animals lacking only the germline (<xref ref-type="bibr" rid="B54">Gerisch et al., 2007</xref>). In addition to regulating DAF-16 cellular localization, DAF-12 also activates the fatty acid reductase <italic>fard-1</italic>, a gene required for lifespan extension in animals lacking germline (<xref ref-type="bibr" rid="B112">McCormick et al., 2012</xref>).</p>
<p>The intestine is a key site where DAF-16 exerts its effects. While DAF-16 is present in both muscles and neurons, its activity in extending lifespan upon germline removal is specifically required in the intestine (<xref ref-type="bibr" rid="B103">Libina et al., 2003</xref>). Targets of DAF-16 include genes involved in proteolysis <italic>rpn-6</italic>, a subunit of the proteasome (<xref ref-type="bibr" rid="B169">Vilchez et al., 2012</xref>). DAF-16 can form a complex with the transcription factor HLH-30 (mammalian TFEB), leading to the joint regulation of a shared group of promoters (<xref ref-type="bibr" rid="B105">Lin et al., 2018</xref>), or independently regulating their specific targets (<xref ref-type="bibr" rid="B105">Lin et al., 2018</xref>). Proteostasis is also regulated by endogenous siRNAs that activate stress-responsive genes through the heat-shock transcription factor HSF-1 (<xref ref-type="bibr" rid="B30">Cohen-Berkman et al., 2020</xref>).</p>
<p>Together with TCER, DAF-16 regulates lipid homeostasis (<xref ref-type="bibr" rid="B57">Ghazi et al., 2009</xref>; <xref ref-type="bibr" rid="B3">Amrit et al., 2016</xref>). Among the genes regulated by these factors are lipases <italic>lipl-1</italic> and <italic>lipl-2</italic> [90, lips-17 {McCormick, 2012 &#x23;10478], the fatty acid desaturase <italic>fat-5</italic> (<xref ref-type="bibr" rid="B59">Goudeau et al., 2011</xref>; <xref ref-type="bibr" rid="B112">McCormick et al., 2012</xref>), and the fatty acid elongase <italic>elo-2</italic> (<xref ref-type="bibr" rid="B112">McCormick et al., 2012</xref>). A DAF-16 target, the lipase LIPL-4 (<xref ref-type="bibr" rid="B173">Wang et al., 2008</xref>; <xref ref-type="bibr" rid="B119">Mony et al., 2021</xref>), activates the nuclear hormone receptor NHR-49 (mammalian PPAR&#x251;) (<xref ref-type="bibr" rid="B42">Folick et al., 2015</xref>). NHR-49 is necessary for lifespan extension in <italic>C. elegans</italic> lacking germline, and it upregulates the expression of genes involved in <italic>de novo</italic> fat synthesis (<xref ref-type="bibr" rid="B142">Ratnappan et al., 2014</xref>). LIPL-4 also induces autophagy by upregulating the activity of the transcription factor PHA-4 (<xref ref-type="bibr" rid="B94">Lapierre et al., 2011</xref>).</p>
<p>The nuclear hormone receptor, NHR-80 (<xref ref-type="bibr" rid="B59">Goudeau et al., 2011</xref>), together with NHR-49, is activated by LIPL-4 (<xref ref-type="bibr" rid="B42">Folick et al., 2015</xref>). Following a common theme from the transcriptional regulators mentioned above, NHR-80 regulates lipid metabolism by controlling the expression of desaturases, requiring DAF-12 (<xref ref-type="bibr" rid="B59">Goudeau et al., 2011</xref>). Likewise, the transcription factor SKN-1 is activated in the intestine upon germline removal and regulates lipid metabolism and stress resistance (<xref ref-type="bibr" rid="B156">Steinbaugh et al., 2015</xref>). The activation of SKN-1 is mediated by the generation of redox species and H<sub>2</sub>S, enabled by KRI-1 (<xref ref-type="bibr" rid="B176">Wei and Kenyon, 2016</xref>). How exactly KRI-1 changes the redox chemistry is not known.</p>
<p>In summary, fat-processing enzymes are overrepresented in <italic>C. elegans</italic> without a proliferating germline (<xref ref-type="bibr" rid="B173">Wang et al., 2008</xref>; <xref ref-type="bibr" rid="B59">Goudeau et al., 2011</xref>; <xref ref-type="bibr" rid="B113">McCormick and Kennedy, 2012</xref>). Some of those enzymes (e.g., LIPL-4), when constitutively expressed, result in lifespan extension (<xref ref-type="bibr" rid="B173">Wang et al., 2008</xref>). Although initially it was proposed that the main benefit of lipids was the result of catabolism processes (<xref ref-type="bibr" rid="B173">Wang et al., 2008</xref>), it was later found that the synthesis of lipids was also important (see next section).</p>
</sec>
<sec id="s5">
<title>Changes in lipid metabolism in <italic>C. elegans</italic> lacking a proliferating germline</title>
<p>One of the hallmarks of <italic>C. elegans</italic> lacking a proliferating germline is the remodeling of lipid distribution and metabolism (<xref ref-type="bibr" rid="B126">O&#x2019;Rourke et al., 2009</xref>; <xref ref-type="bibr" rid="B173">Wang et al., 2008</xref>; <xref ref-type="bibr" rid="B64">Hansen et al., 2013</xref>; <xref ref-type="bibr" rid="B25">Bustos and Partridge, 2017</xref>; <xref ref-type="bibr" rid="B171">Wan et al., 2019</xref>). Lipids are structurally diverse, but share common biophysical properties such as hydrophobicity. They have multiple functions, including roles as components of cellular structures, signaling molecules, and energy storage (<xref ref-type="bibr" rid="B121">Mutlu et al., 2021</xref>). <italic>C. elegans</italic> lipid constitution and metabolism were reviewed recently (<xref ref-type="bibr" rid="B175">Watts and Ristow, 2017</xref>; <xref ref-type="bibr" rid="B5">An et al., 2023</xref>), as well as their role in aging (<xref ref-type="bibr" rid="B130">Papsdorf and Brunet, 2019</xref>; <xref ref-type="bibr" rid="B131">Parkhitko et al., 2020</xref>; <xref ref-type="bibr" rid="B121">Mutlu et al., 2021</xref>; <xref ref-type="bibr" rid="B23">Bresgen et al., 2023</xref>).</p>
<p>The cholesterol-derived hormone dafachronic acid (DA) is critical for <italic>glp-1</italic> lifespan extension by enhancing the activity of the transcription factor DAF-12. The enzyme DAF-9, essential for the synthesis of DA, is expressed in the somatic gonad. This evidence is suggestive of the role of DA as the somatic pro-longevity signal in germline-less <italic>C. elegans</italic> (<xref ref-type="bibr" rid="B178">Yamawaki et al., 2010</xref>). A simple model is that somatic gonad can stimulate DA production when the germline cells are removed. However, although an initial report indicated an increase in the concentration of DA in <italic>glp-1</italic> mutants (<xref ref-type="bibr" rid="B147">Shen et al., 2012</xref>), more sensitive detection methods have disputed these findings (<xref ref-type="bibr" rid="B102">Li et al., 2015</xref>). It is thus yet unknown how DAF-12 activity towards the ligand is increased in <italic>glp-1</italic> mutants.</p>
<p>The composition of lipids is influenced by enzymes involved in the processes of fatty acid elongation, desaturation, &#x3b2;-oxidation, and lipase activity. In <italic>glp-1</italic> mutants, the elongase ELO-3 is critical for the activation of SKN-1 (but not for the activation of DAF-16 or HSF-1) (<xref ref-type="bibr" rid="B172">Wang et al., 2021</xref>). Synthesis of a lipid intermediate by ELO-3 results in changes in the membrane of lysosomes, ultimately suppressing a nutrient-sensing pathway that promotes the activation of SKN-1 (<xref ref-type="bibr" rid="B172">Wang et al., 2021</xref>). Together with NHR-49 (<xref ref-type="bibr" rid="B142">Ratnappan et al., 2014</xref>), SKN-1 upregulates genes involved in mitochondrial &#xdf;-oxidation (<xref ref-type="bibr" rid="B156">Steinbaugh et al., 2015</xref>) in <italic>glp-1</italic> mutants, generating energy and reducing lipid storage. The lysosomal lipase LIPL-4 also increases levels of mitochondrial &#xdf;-oxidation, apparently independently of SKN-1. LIPL-4, which is required for lifespan extension in <italic>glp-1</italic> animals (<xref ref-type="bibr" rid="B173">Wang et al., 2008</xref>), generates oleoylethanolamide (OEA) (<xref ref-type="bibr" rid="B42">Folick et al., 2015</xref>). OEA is a monounsaturated fatty acid that binds to the lipid chaperone LBP-8, which induces nuclear translocation of NHR-80 and NHR-49 (<xref ref-type="bibr" rid="B42">Folick et al., 2015</xref>). These transcription factors activate genes in the mitochondria responsible for &#xdf;-oxidation (<xref ref-type="bibr" rid="B139">Ramachandran et al., 2019</xref>). Consistent with the importance of mitochondrial &#xdf;-oxidation for lifespan extension, inhibition of this process in <italic>glp-1</italic> mutants results in a shorter lifespan (<xref ref-type="bibr" rid="B109">Macedo et al., 2020</xref>).</p>
<p>The <italic>C. elegans fat-5, fat-6,</italic> and <italic>fat-7</italic> genes encode &#x394;9-desaturases, which preferentially convert saturated C16:0 and C18:0 fatty acids to the monounsaturated C16:1 and C18:1 fatty acids (<xref ref-type="bibr" rid="B174">Watts and Browse, 2000</xref>), have repeatedly been found to be upregulated after removing the germline (<xref ref-type="bibr" rid="B59">Goudeau et al., 2011</xref>; <xref ref-type="bibr" rid="B142">Ratnappan et al., 2014</xref>; <xref ref-type="bibr" rid="B156">Steinbaugh et al., 2015</xref>; <xref ref-type="bibr" rid="B3">Amrit et al., 2016</xref>). Dietary supplementation with monounsaturated fatty acids (MUFAs), such as oleic, palmitoleic, or cis&#x2010;vaccenic acids, is sufficient to increase lifespan (<xref ref-type="bibr" rid="B63">Han et al., 2017</xref>; <xref ref-type="bibr" rid="B96">Lee et al., 2019</xref>), and their presence is abundant in other long-lived <italic>C. elegans</italic> mutants (<xref ref-type="bibr" rid="B149">Shmookler Reis et al., 2011</xref>). It is not yet clear how MUFAs regulate lifespan, but they have suggested roles in promoting membrane fluidity, enhancing energy storage, and minimizing oxidative stress (<xref ref-type="bibr" rid="B91">Koyiloth and Gummadi, 2022</xref>).</p>
<p>The role of lipids in lifespan extension is an area of active investigation, which is complicated by the fact that these molecules are pleiotropic, as well as being very diverse in structure and function. Lipid remodeling also occurs in other sterility mutants (<xref ref-type="bibr" rid="B26">Chaturbedi and Lee, 2023</xref>), although it does not result in lifespan extension at 20&#xb0;C (<xref ref-type="bibr" rid="B78">Kenyon et al., 1993</xref>; <xref ref-type="bibr" rid="B10">Arantes-Oliveira et al., 2002</xref>; <xref ref-type="bibr" rid="B26">Chaturbedi and Lee, 2023</xref>). Recent lipidomic and transcriptomic analysis showed that lower sphingosine levels correlate with a longer lifespan (<xref ref-type="bibr" rid="B26">Chaturbedi and Lee, 2023</xref>), but the significance of this correlation still needs to be determined.</p>
</sec>
<sec id="s6">
<title>Prolonged lifespan and reproductive quiescence in starved <italic>C. elegans</italic>
</title>
<p>Our discussions have so far centered on lifespan extension through germline removal by artificial means. It is interesting to note that lifespan can also extend naturally, particularly under conditions like food scarcity. <italic>C. elegans</italic>, with its rapid reproductive cycle and short generation time, faces frequent food shortages (<xref ref-type="bibr" rid="B145">Schulenburg and Felix, 2017</xref>). This nematode has developed adaptations to survive these events, with its response to food availability varying depending on the developmental stage when food becomes scarce [for review, see (<xref ref-type="bibr" rid="B17">Baugh and Hu, 2020</xref>; <xref ref-type="bibr" rid="B140">Rashid et al., 2020</xref>)]. Understanding these natural adaptive responses offers valuable insights into lifespan regulation.</p>
<p>Dietary restriction, which includes caloric restriction, intermittent fasting, and food deprivation, is a well-known condition that modulates lifespan (<xref ref-type="bibr" rid="B106">Loo et al., 2023</xref>). When food deprivation (FD) is limited to adulthood, it results in a 50% increase in lifespan (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B75">Kaeberlein et al., 2006</xref>; <xref ref-type="bibr" rid="B97">Lee et al., 2006</xref>). Animals lacking proliferating germline (e.g., <italic>glp-1</italic> mutants) on FD do not show a further lifespan increase (<xref ref-type="bibr" rid="B164">Thondamal et al., 2014</xref>), indicating that the somatic gonad signal and the diet restriction pathways may converge to the same downstream mechanisms (<xref ref-type="bibr" rid="B33">Crawford et al., 2007</xref>; <xref ref-type="bibr" rid="B164">Thondamal et al., 2014</xref>).</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption>
<p>A <italic>glp-1</italic> mutation and ARD additively extend longevity. Animals can be subjected to diet restriction during adulthood or late larval stages (ARD). Food deprivation (FD) during adulthood does not increase lifespan in <italic>glp-1</italic> mutants but in ARD conditions.</p>
</caption>
<graphic xlink:href="fragi-05-1380016-g001.tif"/>
</fig>
<p>
<italic>C. elegans</italic> molts four times, going through larval stages named L1-L4 before becoming a reproducing adult. However, lack of food and other environmental conditions (e.g., pheromones, high temperatures) experienced by late L1 larvae results in the development of the L2d stage, followed by a non-feeding alternative stage called &#x201c;dauer&#x201d; (<xref ref-type="bibr" rid="B58">Golden and Riddle, 1984</xref>). In <italic>C. elegans</italic>, the dauer stage can last for up to a few months (<xref ref-type="bibr" rid="B87">Klass and Hirsh, 1976</xref>), a period during which the germline stops proliferating and remains undifferentiated. The process of dauer entry involves a rewiring of the metabolism (<xref ref-type="bibr" rid="B133">Penkov et al., 2020</xref>), including upregulation of genes involved in stress response and downregulation of genes involved in growth (<xref ref-type="bibr" rid="B29">Cohen et al., 2021</xref>). Despite active <italic>glp-1</italic> activity (<xref ref-type="bibr" rid="B146">Seidel and Kimble, 2015</xref>), germline stem cells arrest the cell cycle and require the PTEN tumor suppressor DAF-18 as well as LKB1/AMPK (AMP-activated protein kinase) signaling to maintain cell cycle quiescence (<xref ref-type="bibr" rid="B124">Ogg et al., 1998</xref>; <xref ref-type="bibr" rid="B122">Narbonne and Roy, 2006</xref>; <xref ref-type="bibr" rid="B163">Tenen and Greenwald, 2019</xref>). Larvae that hatch in the absence of food do not form dauers, but arrest development as L1 for up to 21&#xa0;days (<xref ref-type="bibr" rid="B72">Johnson et al., 1984</xref>; <xref ref-type="bibr" rid="B98">Lee et al., 2012</xref>; <xref ref-type="bibr" rid="B16">Baugh, 2013</xref>). Germ cell arrest in this stage is also dependent on DAF-18 and AMPK (<xref ref-type="bibr" rid="B45">Fukuyama et al., 2006</xref>; <xref ref-type="bibr" rid="B46">Fukuyama et al., 2012</xref>), but does not require DAF-16 (<xref ref-type="bibr" rid="B18">Baugh and Sternberg, 2006</xref>; <xref ref-type="bibr" rid="B45">Fukuyama et al., 2006</xref>).</p>
<p>When starved in the late larval stages (e.g., L3 and L4), <italic>C. elegans</italic> reaches adulthood with a reduced number of germline cells that remain arrested in their cell division and differentiation (<xref ref-type="bibr" rid="B7">Angelo and Van Gilst, 2009</xref>; <xref ref-type="bibr" rid="B144">Schindler et al., 2014</xref>; <xref ref-type="bibr" rid="B146">Seidel and Kimble, 2015</xref>; <xref ref-type="bibr" rid="B55">Gerisch et al., 2020</xref>). This adult in reproductive diapause (ARD) lives almost three times the normal worm lifespan (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B7">Angelo and Van Gilst, 2009</xref>; <xref ref-type="bibr" rid="B55">Gerisch et al., 2020</xref>). Once food becomes available, the germline starts to proliferate and the animal resumes to undergo a normal lifespan. <italic>glp-1</italic> mutants submitted to ARD live even longer (<xref ref-type="fig" rid="F1">Figure 1</xref>), indicating that gonad signaling and ARD act through different pathways.</p>
<p>Molecular studies indicate some overlap between the germline pathway and ARD. Similar to <italic>glp-1</italic> mutants that lack a proliferating germline, ARD animals require HLH-30 and DAF-16 for lifespan extension (<xref ref-type="bibr" rid="B55">Gerisch et al., 2020</xref>). HLH-30 directly upregulates some genes involved in fat metabolism, such as <italic>fat-5</italic>, <italic>fat-6</italic>, <italic>nhr-80</italic>, and <italic>lipl-3</italic> (<xref ref-type="bibr" rid="B55">Gerisch et al., 2020</xref>). However, reduced activities of DAF-12, dafachronic acid, SKN-1, NHR-49, PHA-4, and HSF-1, which are necessary for the lifespan extension of <italic>glp-1</italic> mutants, had little or no effect on ARD lifespan (<xref ref-type="bibr" rid="B55">Gerisch et al., 2020</xref>). NHR-49, however, may be required for the initiation of ARD (<xref ref-type="bibr" rid="B38">Eustice et al., 2022</xref>).</p>
<p>In summary, food deprivation during late larval stages results in adults in reproductive diapause (ARD) that superficially resemble germline-ablated animals and mutants for germline proliferation. Although they share the lack of dividing germ cells, the extent of the longevity and molecular mechanisms seem to be different. It is possible that other ecologically relevant scenarios better mimic germline ablation. Nevertheless, it would be interesting to further investigate the molecular mechanisms underlying ARD to understand lifespan extension in a more natural context.</p>
</sec>
<sec id="s7">
<title>The effects of germline removal in other nematodes</title>
<p>To understand the generality of mechanisms behind lifespan extension in mutants lacking germline, a comparative analysis is necessary. Recent research has shown that early reproductive efforts are linked to pathologies emerging at post-reproductive age. Hermaphrodites from species of the <italic>Caenorhabditis</italic> and <italic>Pristionchus</italic> genera that can reproduce with males (androdioecious species) die sooner than their relatives that have females and males (gonochoristic species) (<xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>) (<xref ref-type="fig" rid="F2">Figure 2</xref>). This earlier death of hermaphrodites is largely attributed to the significant amount of energy expended in producing yolk (<xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>).</p>
<fig id="F2" position="float">
<label>FIGURE 2</label>
<caption>
<p>Germline ablation results in significant lifespan extension in hermaphrodites of most androdioecious species. Phylogeny of nematodes showing androdioecious species in red font. The arrow indicates the species that show significant lifespan extension after removing the germline, either by Z2/Z3 ablation or by performing <italic>glp-1</italic> RNAi. Strain names are in parenthesis. The phylogenetic tree was adapted from (<xref ref-type="bibr" rid="B85">Kiontke et al., 2005</xref>; <xref ref-type="bibr" rid="B160">Susoy et al., 2016</xref>; <xref ref-type="bibr" rid="B157">Stevens et al., 2019</xref>). <italic>D. coronatus</italic> is an outgroup and no germline ablation experiments were performed in this species.</p>
</caption>
<graphic xlink:href="fragi-05-1380016-g002.tif"/>
</fig>
<p>In most androdioecious species studied, removing the germline in hermaphrodites led to a significant increase in lifespan (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>; <xref ref-type="bibr" rid="B132">Patel et al., 2002</xref>; <xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>). In contrast, corresponding experiments in gonochoristic sibling species resulted in little or no lifespan extension in females (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>; <xref ref-type="bibr" rid="B132">Patel et al., 2002</xref>; <xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>). The germline removal in hermaphrodites may suppress &#x201c;reproductive death,&#x201d; a rapid death process typically caused by the intense demands of reproduction (<xref ref-type="bibr" rid="B52">Gems et al., 2021</xref>). This type of death is considered programmatic rather than random, as signals from the somatic gonad can modulate it. Indeed, removing the entire gonad in hermaphroditic species does not delay senescence onset, whereas germline ablation does, indicating counteracting signals between the gonad tissues (<xref ref-type="bibr" rid="B81">Kern et al., 2021</xref>).</p>
<p>In hermaphrodites of androdioecious species, a common senescent pathology during aging is excessive yolk production by the intestine (<xref ref-type="bibr" rid="B39">Ezcurra et al., 2018</xref>; <xref ref-type="bibr" rid="B154">Sornda et al., 2019</xref>; <xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>). This yolk overproduction leads to intestinal atrophy, driven by extensive autophagy and lipophagy, which are essential processes for generating the biomass necessary for lipoprotein synthesis (<xref ref-type="bibr" rid="B39">Ezcurra et al., 2018</xref>). In contrast, virgin females of gonochoristic species do not exhibit intestinal atrophy or yolk accumulation in the pseudocoelom, typically resulting in a longer lifespan compared to their androdioecious sibling species (<xref ref-type="bibr" rid="B81">Kern et al., 2021</xref>). However, upon mating, these females exhibit aging patterns and pathologies similar to those of hermaphrodites. It has been proposed that the abundant production of yolk may be adaptive in hermaphrodites, as lipoproteins can be released into the environment to serve as a nutritional source for the offspring (<xref ref-type="bibr" rid="B81">Kern et al., 2021</xref>). Mated females release only minimal amounts of yolk, and mating in hermaphrodites similarly decreases the levels of yolk they vent. This reduction is hypothesized to result from the absorption of yolk into oocytes that are fertilized later (<xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>).</p>
<p>Germline removal in non-<italic>Caenorhabditis</italic> nematodes, such as <italic>P. pacificus</italic>, results in gene expression changes and phenotypes that are similar to those found in <italic>C. elegans</italic>. These include the accumulation of fat and upregulation of genes involved in fat metabolism (e.g., <italic>fat-7</italic>), enrichment for DAF-16 targets, and downregulation of the insulin pathway (<xref ref-type="bibr" rid="B136">Rae et al., 2012</xref>). However, whether those changes are functionally relevant for influencing lifespan in <italic>P. pacificus</italic> is unclear. It would be interesting to further investigate the <italic>Oscheius</italic> species since ablation of the germline cells in two of the hermaphroditic species does not seem to extend lifespan (<xref ref-type="bibr" rid="B132">Patel et al., 2002</xref>) (<xref ref-type="fig" rid="F2">Figure 2</xref>). It is possible these species recently evolved hermaphroditism and have yet to develop mechanisms associated with reproductive death. Nematode species that have both hermaphrodites and females may also provide valuable insights (<xref ref-type="bibr" rid="B27">Chaudhuri et al., 2011</xref>; <xref ref-type="bibr" rid="B76">Kanzaki et al., 2017</xref>).</p>
</sec>
<sec id="s8">
<title>Reproduction and the evolution of aging</title>
<p>The concept that there is a trade-off between the probability of death and reproduction underpins the evolutionary theory of aging (<xref ref-type="bibr" rid="B111">Maklakov and Immler, 2016</xref>). According to the &#x201c;disposable soma&#x201d; theory, there is a competition for resources between somatic maintenance and reproduction (<xref ref-type="bibr" rid="B86">Kirkwood, 1991</xref>; <xref ref-type="bibr" rid="B100">Lemaitre et al., 2015</xref>). However, removing germ cells not only extends lifespan but also enhances resistance to a wide range of environmental and biological stressors (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>), contradicting this theory. Lifespan extension as a result of germ cell removal is not restricted to nematodes. The fruitfly <italic>Drosophila</italic> without proliferating germline stem cells shows increased longevity (<xref ref-type="bibr" rid="B41">Flatt et al., 2008</xref>), and gonad removal in vertebrates such as fish also results in extended lifespan (<xref ref-type="bibr" rid="B52">Gems et al., 2021</xref>). Likewise, human eunuchs have been reported to live about 15&#xa0;years longer than non-castrated men (<xref ref-type="bibr" rid="B117">Min et al., 2012</xref>), although the accuracy of these historical records has been challenged on methodological grounds (<xref ref-type="bibr" rid="B95">Le Bourg, 2015</xref>).</p>
<p>Critical to understanding aging is to identify the proximal causes. The disposable soma theory assumes that resources are required to repair somatic tissues and that the accumulation of damage is the proximate cause of aging. Nevertheless, the concept that aging is driven by molecular damage from oxidative damage (<xref ref-type="bibr" rid="B50">Gems and Doonan, 2009</xref>; <xref ref-type="bibr" rid="B134">Perez et al., 2009</xref>; <xref ref-type="bibr" rid="B167">Van Raamsdonk and Hekimi, 2010</xref>), or change in telomere length (<xref ref-type="bibr" rid="B137">Raices et al., 2005</xref>; <xref ref-type="bibr" rid="B32">Cook et al., 2016</xref>) [but see (<xref ref-type="bibr" rid="B71">Joeng et al., 2004</xref>)] lacks empirical support, at least in nematodes. In fact, it has been suggested that many of the elements identified as &#x201c;hallmarks of aging&#x201d; (<xref ref-type="bibr" rid="B107">L&#xf3;pez-Ot&#xed;n et al., 2013</xref>; <xref ref-type="bibr" rid="B108">Lopez-Otin et al., 2023</xref>), which include cellular damage, cannot be generalized to many organisms including <italic>C. elegans</italic> (<xref ref-type="bibr" rid="B49">Gems and de Magalh&#xe3;es, 2021</xref>). It would be useful to identify what are the primary, secondary, and tertiary causes of aging, as well as how they give rise to aging (<xref ref-type="bibr" rid="B49">Gems and de Magalh&#xe3;es, 2021</xref>).</p>
<p>From the work on comparison between the rate of aging in nematodes with different modes of reproduction (<xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>), hermaphrodites seem to undergo a mechanistically non-stochastic (programmatic) aging process (<xref ref-type="bibr" rid="B22">Blagosklonny, 2006</xref>). This is an alternative theory of aging, which proposes that exaggerated investment in reproduction leads to post-reproductive senescent pathologies (<xref ref-type="bibr" rid="B79">Kern and Gems, 2022</xref>). When this investment is prevented by germline removal, hermaphrodites live as long as the females of sister species (which do not have programmatic aging) (<xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>). Interestingly, the most significant lifespan increases following germline removal have been observed in semelparous animals, which show a terminal reproductive effort that leads to their death (<xref ref-type="bibr" rid="B79">Kern and Gems, 2022</xref>). It is thus likely that interventions proven to significantly extend the lifespan of <italic>C. elegans</italic>, such as mutations stopping germline proliferation or the removal of germline cells, might be specific to organisms that experience reproductive death.</p>
<p>Although not addressing directly the evolution of aging, a potentially interesting avenue of research would be to compare the pattern and mechanisms of aging between closely related species. For instance, it would be interesting to determine if transcription factors known to be active in germline-less hermaphrodites are also active in females of sister species, and whether interventions found to increase the lifespan in wild-type hermaphrodites (e.g., constitutive expression of <italic>lipl-4</italic>) has the same effect on females. In species with no reproductive death such as <italic>Drosophila</italic>, similar changes to <italic>C. elegans</italic> occur after germline ablation, such as lifespan extension, fat storage, and lipid enzyme regulation (<xref ref-type="bibr" rid="B156">Steinbaugh et al., 2015</xref>; <xref ref-type="bibr" rid="B143">Rodrigues et al., 2023</xref>). These results would suggest the conservation of mechanisms of lifespan extension, but more research is required to determine this.</p>
</sec>
<sec id="s9">
<title>Concluding remarks and outlook</title>
<p>Some mechanisms explaining the increased longevity of germline-less <italic>C. elegans</italic> are seemingly contradictory. For example, while high autophagy is thought to shorten lifespan in wild-type animals by leading to the consumption of their gut (<xref ref-type="bibr" rid="B39">Ezcurra et al., 2018</xref>; <xref ref-type="bibr" rid="B80">Kern et al., 2023</xref>), long-lived germline-less individuals also exhibit high levels of autophagy (<xref ref-type="bibr" rid="B94">Lapierre et al., 2011</xref>). This discrepancy may be due to different uses of autophagy products in these scenarios, resulting in different outcomes. For instance, <italic>glp-1</italic> animals produce more yolk protein than wild-type animals on the first day of adulthood (<xref ref-type="bibr" rid="B156">Steinbaugh et al., 2015</xref>). However, yolk levels increase substantially with age in wild-type worms, peaking around the seventh day of adulthood (<xref ref-type="bibr" rid="B39">Ezcurra et al., 2018</xref>). This suggests that the elevated yolk in germline-less animals might not result from the same harmful autophagic gut-to-yolk biomass conversion seen in wild-type animals but from the synthesis of fat from other sources. Indeed, a <italic>glp-4</italic> mutation abrogates intestinal atrophy (<xref ref-type="bibr" rid="B39">Ezcurra et al., 2018</xref>), suggesting this autophagic process may not function in the same manner in germline-less animals. An additional possibility is that other mechanisms triggered by the absence of a proliferating germline could compensate for the harmful effects of high autophagy seen in animals with an intact germline.</p>
<p>Most studies have primarily focused on possible pro-longevity factors mediated by the somatic gonad. However, there is now an increasing interest in exploring pro-aging signals mediated by the germline. The Hedgehog signaling pathway, a conserved regulator of animal development (<xref ref-type="bibr" rid="B70">Ingham et al., 2011</xref>), has been recently implicated in this process (<xref ref-type="bibr" rid="B148">Shi and Murphy, 2023</xref>). Germline hyperactivity, triggered by mating, activates the Hedgehog pathway and also mediates the lifespan in other invertebrates (<xref ref-type="bibr" rid="B138">Rallis et al., 2020</xref>).</p>
<p>For a comprehensive understanding of how aging mechanisms work in <italic>C. elegans,</italic> further research should systematically involve both sexes (<xref ref-type="bibr" rid="B6">Ancell and Pires-daSilva, 2017</xref>). For some longevity treatments, there are clear differences between the sexes (<xref ref-type="bibr" rid="B66">Honjoh et al., 2017</xref>). Diet restriction, for example, extends the lifespan of <italic>C. elegans</italic> hermaphrodites, but not of males. The response to diet restriction is mediated by the terminal effector of sex determination TRA-1 (<xref ref-type="bibr" rid="B66">Honjoh et al., 2017</xref>), a transcription factor that promotes longevity in hermaphrodites by upregulating some isoforms of <italic>daf-16</italic> (<xref ref-type="bibr" rid="B67">Hotzi et al., 2018</xref>). The lower. TRA-1 activity in males leads to higher expression of the nuclear receptor DAF-12, resulting in a weaker DR response (<xref ref-type="bibr" rid="B66">Honjoh et al., 2017</xref>).</p>
<p>There is still a large gap in our understanding of the relationship between molecular changes, lifespan, and causes of death. Some of the remaining broader questions include the proximate causes of aging and the causes of pathologies of aging that result in death (<xref ref-type="bibr" rid="B49">Gems and de Magalh&#xe3;es, 2021</xref>), and commonalities of mechanisms of lifespan extension under different conditions (e.g., dauer, L1 arrest, ARD, germline-less) within and between species. For example, it is unclear if regulators of germ cell quiescence in L1 and dauer (DAF-18/PTEN and AMPK) also have a role in the lifespan extension of germline ablated or germ-cell nematodes. It is also unclear why many of the genes necessary for lifespan extension in germline-less animals (e.g., DA/DAF-12 signaling, TCER-1, and lipid metabolism genes) are also required for reduced fecundity in post-dauer adults (<xref ref-type="bibr" rid="B1">Adams et al., 2022</xref>). The identity of the signals that mediate the communication between the soma and germline cells (<xref ref-type="bibr" rid="B31">Conine and Rando, 2022</xref>; <xref ref-type="bibr" rid="B127">Ow and Hall, 2024</xref>), and that could influence lifespan (<xref ref-type="bibr" rid="B68">Hsin and Kenyon, 1999</xref>), are also largely unexplored. Answering these questions will guide the research to formulate hypotheses that could be tested experimentally. For instance, while the accumulation of cellular damage has been a popular paradigm for explaining the primary cause of aging, experimental evidence has raised doubts about its validity (<xref ref-type="bibr" rid="B36">de Magalhaes and Church, 2006</xref>; <xref ref-type="bibr" rid="B50">Gems and Doonan, 2009</xref>; <xref ref-type="bibr" rid="B134">Perez et al., 2009</xref>). Thus, new theories that consider biological constraints (<xref ref-type="bibr" rid="B51">Gems and Kern, 2022</xref>) and that can unite proximal with the ultimate causes of aging (<xref ref-type="bibr" rid="B48">Gems, 2022</xref>) are welcome.</p>
</sec>
</body>
<back>
<sec id="s10">
<title>Author contributions</title>
<p>AP-dS: Conceptualization, Supervision, Writing&#x2013;original draft, Writing&#x2013;review and editing. RK: Writing&#x2013;original draft, Writing&#x2013;review and editing. LR: Writing&#x2013;original draft, Writing&#x2013;review and editing.</p>
</sec>
<sec sec-type="funding-information" id="s11">
<title>Funding</title>
<p>The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Ph.D. training grants from BBSRC to RK and LR and a BBSRC research grant to AP (BB/L019884/1).</p>
</sec>
<sec sec-type="COI-statement" id="s12">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="s13">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
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