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\def\RunningAuthor{Goon Jo Aan et al.}
\firstPage{1762}
\articleType{Original Article}
\receivedDate{09.08.2019}
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\title{Role of insulin/insulin-like growth factor-1 signaling pathway genes on the lifespan of \textit{Caenorhabditis elegans}}
\author{Siti~Bazilah~Zulkefli\textsuperscript{1},  
            Ahmad~Nazrun~Shuid\textsuperscript{2}, 
            Goon~Jo~Aan\textsuperscript{*}\textsuperscript{1}~\\[5pt]{\textsuperscript{1}Department of Biochemistry, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia}~\\{\textsuperscript{2}Pharmaco-Epidemiology Unit, Department of Pharmacology, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia}}

\begin{abstract}
Aging process is influenced by the insulin/insulin-like growth factor-1 signaling (IIS) pathway or IGF-1 signaling pathway. Studies done on the genes of this pathway were found to affect longevity. However, no conclusive results have been drawn. The purpose of this systematic review is to summarize the function of genes involved in the IIS pathway of \textit{Caenorhabditis Elegans } (\textit{C. elegans}), a nematode commonly used as a model organism in molecular genetics and developmental biology. A literature search for relevant studies was done through PubMed and Scopus databases using MeSH keywords \textit{Caenorhabditis elegans}, \textit{C. elegans}, nematode, genes, RNA, DNA, IIS pathway, IGF pathway, lifespan, and longevity. The search was limited to studies that were published in the last ten years (2008-May 2018). After exclusion of duplicates, review papers, human, \textit{in vitro}, and other organismal studies, a total of 76 research articles were selected for further assessments. Data relevant to the effects of IIS genes on the lifespan of \textit{C. elegans} was independently extracted. Reduction of \textit{daf-2} and \textit{age-1} and overexpression of \textit{sir-2.1} were reported to promote increment of the lifespan of \textit{C. elegans. } Furthermore, differentially expressed genes that were involved in the protection against oxidative stress, pathogen attack, and toxicity include \textit{ins-18}\textit{, } \textit{numr-1/-2, sgk-1}, and \textit{rgs-1}. The knockdown of \textit{daf-2}, \textit{age-1}, and overexpression of \textit{sir-2.1} genes prolonged the lifespan of \textit{C. elegans} while knockdown of \textit{daf-16}, \textit{hsf-1}, \textit{sir-2.1} as well as \textit{skn-1} shorten the lifespan of \textit{C. elegans}. In conclusion, the differential expression of genes in the IIS pathway prolongs the lifespan of \textit{C. elegans}. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}C. elegans,\newline DNA,\newline IIS pathway,\newline IGF pathway,\newline lifespan,\newline longevity,\newline nematode,\newline RNA
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Goon~Jo~Aan~\\ Phone:\ +603 9145 9558~\\  Email:\ joaan@ukm.edu.my
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Countless studies have used \textit{Caenorhabditis elegans} (\textit{C. elegans}) as a model organism to determine the role of signaling pathways involved in aging and longevity \unskip~\citep{735632:17464479,735632:17464485,735632:17464478}. \textit{C. elegans} have been widely used as a model organism because of its 83\% homologous genome to human \unskip~\citep{735632:17464498}. Other than that, the nematodes also have similar functions of the neurons, skin, gut, muscles, and other tissues like humans \unskip~\citep{735632:17464472}. \textit{C. elegans} have a rapid life cycle, which is around 3 to 4 weeks. This gives an advantage for plausible observation of life stages in the aging process of the organism. Three major 


\begin{table*}[!htbp]
\caption{\boldmath {Effect of differential genes expression on the mean lifespan of \textit{C. elegans}} }
\label{tw-4f8a6e61da69}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.06890000000000001\linewidth-2\tabcolsep}p{\dimexpr.13459999999999999\linewidth-2\tabcolsep}p{\dimexpr.17729999999999997\linewidth-2\tabcolsep}p{\dimexpr.1324\linewidth-2\tabcolsep}p{\dimexpr.2141\linewidth-2\tabcolsep}p{\dimexpr.2727\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}No. & Author & No. of worms used & Culture conditions & Gene tested & Lifespan (days)\\
\tblmidrule 
1 &
  \unskip~\citep{735632:17464474} &
  No data &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Alg-1(gk214)b \mbox{}\protect\newline Alg-1;daf-2b \mbox{}\protect\newline Alg-1;daf-16b \mbox{}\protect\newline Alg-2(ok304)b \mbox{}\protect\newline Alg-2;daf-2b \mbox{}\protect\newline Alg-2;daf-16b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-16(mu86)b &
  16.28\ensuremath{\pm}2.26 \mbox{}\protect\newline \ensuremath{\downarrow}12.81\ensuremath{\pm}2.36 \mbox{}\protect\newline \ensuremath{\uparrow}31.42\ensuremath{\pm}4.53 \mbox{}\protect\newline \ensuremath{\downarrow}11.35\ensuremath{\pm}1.90 \mbox{}\protect\newline \ensuremath{\uparrow}19.59\ensuremath{\pm}1.38 \mbox{}\protect\newline \ensuremath{\uparrow}38.93\ensuremath{\pm}0.39 \mbox{}\protect\newline \ensuremath{\downarrow}11.73\ensuremath{\pm}0.33 \mbox{}\protect\newline \ensuremath{\uparrow}43.08\ensuremath{\pm}5.76 \mbox{}\protect\newline \ensuremath{\downarrow}12.75\ensuremath{\pm}1.69\\
2 &
  \unskip~\citep{735632:17464520} &
  102-165 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline Liquid \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Eat-2(ad1116)b \mbox{}\protect\newline Hsf-1(sy441)b \mbox{}\protect\newline Mev-1(kn-1)b \mbox{}\protect\newline Sir-2.1(ok434)b &
  19.96\ensuremath{\pm}0.39 \mbox{}\protect\newline \ensuremath{\uparrow}36.64\ensuremath{\pm}0.58 \mbox{}\protect\newline \ensuremath{\downarrow}15.48\ensuremath{\pm}0.21 \mbox{}\protect\newline \ensuremath{\uparrow}29.97\ensuremath{\pm}0.29 \mbox{}\protect\newline \ensuremath{\downarrow}11.73\ensuremath{\pm}0.02 \mbox{}\protect\newline \ensuremath{\downarrow}16.02\ensuremath{\pm}0.11 \mbox{}\protect\newline \ensuremath{\downarrow}17.59\ensuremath{\pm}0.29\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
pathways that have been shown to influence the lifespan of these nematodes are insulin/insulin-like growth factor (IIS or IGF-1), a target of rapamycin (TOR), and germline signaling pathways. Although these pathways involve different sets of transcription factors, there is partial overlapping of mechanisms involved in the aging process.

IIS pathway was the first established lifespan-regulating signaling pathway. The IIS pathway contains many conserved longevity-regulatory components that regulate aging in a DAF-16-dependent manner \unskip~\citep{735632:17464504,735632:17464497}. TOR is a mechanistic target of rapamycin, and a serine/threonine kinase that regulates cell growth, proliferation, motility and survival, protein synthesis, autophagy, and transcription. TOR is activated under nutrient- and energy-sufficient conditions, which in turn stimulates growth. Inhibition of TOR signaling was found to increase the lifespan of \textit{C. elegans} in a DAF-16-dependent manner \unskip~\citep{735632:17464495}. Similar to the IIS pathway, DAF-16/FOXO is also required for the lifespan extension of germline-less animals \unskip~\citep{735632:17464475}. Translocation of DAF-16/FOXO to the nucleus in intestinal cells promotes longevity through germline signaling \unskip~\citep{735632:17464496}.

Many studies have reported on the different roles of genes in the IIS pathway. The changes in expression of these genes affects the longevity of \textit{C. elegans} differently depending on the species of nematode used and experimental conditions. The purpose of this review is to summarize the effect of IIS pathway genes to the lifespan of \textit{C. elegans} systematically.

\textbf{Materials and Methods}

An electronic search of the PubMed and Scopus databases were carried out using the keywords: ``\textit{Caenorhabditis elegans''} OR ``\textit{C. elegans}" OR "nematode" AND "genes" OR "RNA" OR "DNA" AND "insulin/insulin-like pathway" OR "IIS pathway" OR "IGF pathway" AND "lifespan" AND "longevity." The search was limited to studies that were published in the last ten years (2008-May 2018). All titles and abstracts were screened after exclusion of duplicates, review papers, ``human," ``in vitro'' and other organismal studies and papers published in languages other than English. After the filtering process, a total of 84 research articles were used for this study. However, the full text of 8 articles were not retrievable due to unavailability, leaving only 76 articles included in this review (Figure~\ref{f-3b1844cbfd59}). The studies were compiled for data extraction. Data relevant to the effects of IIS pathway genes on the lifespan of \textit{C. elegans} were independently extracted (Tables~\ref{tw-4f8a6e61da69}, \ref{tw-5b0514543faf}, \ref{tw-1f2f4ec88855}, \ref{tw-b9eb2520c33b}, \ref{tw-e07c50bb4638}, \ref{tw-cc6c28da7127}, \ref{tw-2c4b854faa9f} and~\ref{tw-6195af99a064}). 
    
\section{Results and Discussion}
Multiple studies, along the years, have shown that lifespan expansion in \textit{C. elegans} mostly correlated with daf-16 transcription via the IIS pathway. Single mutation of IIS genes such as \textit{daf-2}, \textit{age-1}, or \textit{daf-16} leads to inhibition of the IIS pathway and extension of lifespan \unskip~\citep{735632:17464515}. In this review, most studies were found to be done on \textit{daf-2}, \textit{daf-16, }


\begingroup
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\caption{\boldmath {(\textit{Continue from Table 1}) Effect of differential genes expression on the mean lifespan of\textit{ C. elegans }} }
\label{tw-5b0514543faf}
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\tbltoprule \rowcolor{kwdboxcolor}No. & Author & No. of worms used & Culture conditions & Gene tested & Lifespan (days)\\
\tblmidrule 
3 &
  \unskip~\citep{735632:17464521} &
  No data  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline Liquid \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Cand-1b \mbox{}\protect\newline Lin-23b \mbox{}\protect\newline Spg-7b \mbox{}\protect\newline Cand-1;spg-7(ek25)b \mbox{}\protect\newline Ppgn-1b \mbox{}\protect\newline Ppgn-1;spg-7b \mbox{}\protect\newline Eat-3b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-2;eat-3b \mbox{}\protect\newline Fzo-1b \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Eat-2(ad1116)b \mbox{}\protect\newline Eat-2;eat-3b \mbox{}\protect\newline Glp-1b \mbox{}\protect\newline Glp-1;eat-3b &
  28.0 \mbox{}\protect\newline \ensuremath{\uparrow}35.0 \mbox{}\protect\newline \ensuremath{\uparrow}38.0 \mbox{}\protect\newline \ensuremath{\uparrow}31.0 \mbox{}\protect\newline \ensuremath{\uparrow}31.0 \mbox{}\protect\newline \ensuremath{\uparrow}34.0 \mbox{}\protect\newline \ensuremath{\uparrow}41.0 \mbox{}\protect\newline No effect  \mbox{}\protect\newline \ensuremath{\uparrow}70.0 \mbox{}\protect\newline \ensuremath{\uparrow}41.0 \mbox{}\protect\newline \ensuremath{\downarrow}22.0 \mbox{}\protect\newline \ensuremath{\downarrow}25.0 \mbox{}\protect\newline \ensuremath{\uparrow}40.0 \mbox{}\protect\newline \ensuremath{\downarrow}21.0 \mbox{}\protect\newline \ensuremath{\uparrow}45.0 \mbox{}\protect\newline No effect \\
4 &
  \unskip~\citep{735632:17464517} &
  30 &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Rgs-1(nr2017)b \mbox{}\protect\newline Age-1(hx546)b \mbox{}\protect\newline Age-1;rgs-1b \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Daf-16;rgs-1b  &
  15.8\ensuremath{\pm}2.5 \mbox{}\protect\newline \ensuremath{\uparrow}18.8\ensuremath{\pm}2.8 \mbox{}\protect\newline \ensuremath{\uparrow}32.1\ensuremath{\pm}8.9 \mbox{}\protect\newline \ensuremath{\uparrow}32.8\ensuremath{\pm}8.0 \mbox{}\protect\newline \ensuremath{\downarrow}6.6\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\downarrow}6.5\ensuremath{\pm}0.8\\
5 &
  \unskip~\citep{735632:17464522} &
  50 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Age-1(hx546)b \mbox{}\protect\newline Daf-16(mgdf50)b \mbox{}\protect\newline Skn-1(zu169)b \mbox{}\protect\newline Sir-2.1(ok434)b &
  18.90\ensuremath{\pm}0.24 \mbox{}\protect\newline \ensuremath{\uparrow}32.62\ensuremath{\pm}0.08 \mbox{}\protect\newline \ensuremath{\uparrow}29.79\ensuremath{\pm}0.14 \mbox{}\protect\newline \ensuremath{\downarrow}16.73\ensuremath{\pm}0.20 \mbox{}\protect\newline \ensuremath{\downarrow}18.32\ensuremath{\pm}0.26 \mbox{}\protect\newline \ensuremath{\downarrow}13.90\ensuremath{\pm}0.06\\
6 &
  \unskip~\citep{735632:17464523} &
  40 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2b \mbox{}\protect\newline Mbk-1(pk1389)b \mbox{}\protect\newline Hpk-1(pk1393)b &
  20.56\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}49.40\ensuremath{\pm}1.2 \mbox{}\protect\newline \ensuremath{\downarrow}19.21\ensuremath{\pm}0.28 \mbox{}\protect\newline \ensuremath{\downarrow}15.37\ensuremath{\pm}0.28\\
7 &
  \unskip~\citep{735632:17464526} &
  30-40 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Eat-2(ad1116)b \mbox{}\protect\newline Isp-1(qm150)b \mbox{}\protect\newline Sir-2.1(ok434)c \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Rrf-3(pk1426)b \mbox{}\protect\newline Rict-1(mg360)b \mbox{}\protect\newline Hsf-1(sy441)b \mbox{}\protect\newline Age-1(hx546)b \mbox{}\protect\newline Age-1(am88)b &
  15.9\ensuremath{\pm}5.0 \mbox{}\protect\newline \ensuremath{\uparrow}17.9\ensuremath{\pm}5.1 \mbox{}\protect\newline \ensuremath{\uparrow}20.0\ensuremath{\pm}6.4 \mbox{}\protect\newline \ensuremath{\uparrow}17.0\ensuremath{\pm}3.7 \mbox{}\protect\newline \ensuremath{\downarrow}12.6\ensuremath{\pm}3.5 \mbox{}\protect\newline \ensuremath{\uparrow}35.4\ensuremath{\pm}8.9 \mbox{}\protect\newline \ensuremath{\downarrow}15.7\ensuremath{\pm} 4.0 \mbox{}\protect\newline \ensuremath{\downarrow}12.1\ensuremath{\pm}2.6 \mbox{}\protect\newline \ensuremath{\downarrow}11.5\ensuremath{\pm}1.9 \mbox{}\protect\newline \ensuremath{\uparrow}20.7\ensuremath{\pm}6.4 \mbox{}\protect\newline \ensuremath{\uparrow}22.9\ensuremath{\pm}6.2\\
8 &
  \unskip~\citep{735632:17464473} &
  50 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Eat-2(ad1116)b \mbox{}\protect\newline Mev-1(kn1)b \mbox{}\protect\newline Sgk-1(ok538)b \mbox{}\protect\newline Daf-16(mgDf50)b \mbox{}\protect\newline Skn-1(zu67)b \mbox{}\protect\newline Hsf-1(sy441)b  &
  13.7\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\downarrow}9.15\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\uparrow}17.06\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\downarrow}11.09\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}11.69\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}10.20\ensuremath{\pm}0.25\\
9 &
  \unskip~\citep{735632:17464527} &
  90 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Mev-1b \mbox{}\protect\newline Daf-2b \mbox{}\protect\newline Daf-16b \mbox{}\protect\newline Hsf-1b \mbox{}\protect\newline Skn-1b &
  12\ensuremath{\pm}1.15 \mbox{}\protect\newline \ensuremath{\downarrow}10\ensuremath{\pm}1.00 \mbox{}\protect\newline \ensuremath{\uparrow}22\ensuremath{\pm}1.75 \mbox{}\protect\newline \ensuremath{\downarrow}10\ensuremath{\pm}0.57 \mbox{}\protect\newline \ensuremath{\downarrow}8\ensuremath{\pm}1.15 \mbox{}\protect\newline \ensuremath{\downarrow}9\ensuremath{\pm}0.86\\
10 &
  \unskip~\citep{735632:17464537} &
  60 &
  21.5\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli K-12  &
  N2a \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Daf-16;daf-2b  &
  13.9\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}26.4\ensuremath{\pm}0.9 \mbox{}\protect\newline No numerical data \mbox{}\protect\newline \ensuremath{\downarrow}12.7\ensuremath{\pm}0.3 \\
11 &
  \unskip~\citep{735632:17464536} &
  40-50 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Skn-1(zu67)b \mbox{}\protect\newline Daf-16(mgDf50)b \mbox{}\protect\newline Daf-2(el368)b \mbox{}\protect\newline Age-1(hx546)b \mbox{}\protect\newline Sir-2.1(ok434)b \mbox{}\protect\newline Mek-1(ks54)b  &
  14.2\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}11.6\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}12.6\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}17.1\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\uparrow}17.4\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\downarrow}12.1\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}10.9\ensuremath{\pm}0.3\\
12 &
  \unskip~\citep{735632:17464528} &
  15 &
  15\ensuremath{^\circ}C \mbox{}\protect\newline *NGM-Lite \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Sgk-1gf(ft15)b \mbox{}\protect\newline Hsf-1b &
  24.74\ensuremath{\pm}0.55 \mbox{}\protect\newline \ensuremath{\uparrow}32.31\ensuremath{\pm}0.65 \mbox{}\protect\newline \ensuremath{\downarrow}21.83\ensuremath{\pm}1.01 \mbox{}\protect\newline \ensuremath{\downarrow}22.72\ensuremath{\pm}1.07\\
13 &
  \unskip~\citep{735632:17464621} &
  100 &
  23\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli HT115(DE3) &
  N2a \mbox{}\protect\newline Shc-1(ok198)b \mbox{}\protect\newline Shc-1(ok198)c \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Shc-1;daf-16b \mbox{}\protect\newline Shc-1;fer-15(b26)b \mbox{}\protect\newline Fer-15b \mbox{}\protect\newline Daf-16(mgDf50);fer-15b \mbox{}\protect\newline Daf-16 shc-1;fer-15b \mbox{}\protect\newline Jnk-1(gk7)b \mbox{}\protect\newline Shc-1;jnk-1b &
  14.4\ensuremath{\pm}0.1 \mbox{}\protect\newline \ensuremath{\downarrow}38\% (8.9\ensuremath{\pm}0.1) \mbox{}\protect\newline \ensuremath{\uparrow}42\% \mbox{}\protect\newline \ensuremath{\uparrow}15.4\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}10.8\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}10.5\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\downarrow}14.0\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\downarrow}10.1\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\downarrow}10.2\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}11.6\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\downarrow}10.9\ensuremath{\pm}0.1\\
14 &
  \unskip~\citep{735632:17464538} &
  120 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Ife-2(ok306)b \mbox{}\protect\newline Clk-1(qm30)b \mbox{}\protect\newline Eat-2(ad1113)b &
  20.0\ensuremath{\pm}0 \mbox{}\protect\newline \ensuremath{\uparrow}43.0\ensuremath{\pm}0 \mbox{}\protect\newline \ensuremath{\uparrow}29.0\ensuremath{\pm}1.4 \mbox{}\protect\newline \ensuremath{\uparrow}25.0\ensuremath{\pm}0 \mbox{}\protect\newline \ensuremath{\uparrow}26.5\ensuremath{\pm}2.1\\
15 &
  \unskip~\citep{735632:17464511} &
  80-100 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Mev-1(kn-1)b \mbox{}\protect\newline Daf-16(mgdf50)b \mbox{}\protect\newline Sir-2.1(ok434)c \mbox{}\protect\newline Skn-1(zu135)b \mbox{}\protect\newline Eat-2(ad1116)b &
  16.56\ensuremath{\pm}0.26 \mbox{}\protect\newline \ensuremath{\downarrow}12.42\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}14.19\ensuremath{\pm}07 \mbox{}\protect\newline \ensuremath{\uparrow}17.80\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}19.21\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\downarrow}14.98\ensuremath{\pm}0.4\\
\multicolumn{1}{p{\dimexpr(.08849999999999998\linewidth-2\tabcolsep)}}{\multirow{3}{\linewidth}{16}} &
  \multicolumn{1}{p{\dimexpr(.15309999999999997\linewidth-2\tabcolsep)}}{\multirow{3}{\linewidth}{\unskip~\citep{735632:17464539}}} &
  \multicolumn{1}{p{\dimexpr(.15540000000000001\linewidth-2\tabcolsep)}}{\multirow{3}{\linewidth}{150}} &
  15\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-41(ok3052)b \mbox{}\protect\newline Daf-41(ok3015)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Pges-2(ok3316)b \mbox{}\protect\newline Gst-4\&msp-38(ok2358)b &
  30.7\ensuremath{\pm}0.8 \mbox{}\protect\newline \ensuremath{\downarrow}21.8\ensuremath{\pm}0.8 \mbox{}\protect\newline \ensuremath{\downarrow}25.0\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}46.3\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\downarrow}25.0\ensuremath{\pm}1.2 \mbox{}\protect\newline \ensuremath{\downarrow}30.6\ensuremath{\pm}1.3\\
 &
   &
   &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-41b \mbox{}\protect\newline Daf-41b \mbox{}\protect\newline Daf-2b \mbox{}\protect\newline Pges-2b \mbox{}\protect\newline Gst-4\&msp-38b &
  22.6 \ensuremath{\pm} 0.4 \mbox{}\protect\newline \ensuremath{\downarrow}20.9\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}23.3\ensuremath{\pm}0.0 \mbox{}\protect\newline \ensuremath{\uparrow}41.5\ensuremath{\pm}4.7 \mbox{}\protect\newline \ensuremath{\downarrow}20.1\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\uparrow}23.6\ensuremath{\pm}0.5\\
 &
   &
   &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-41b \mbox{}\protect\newline Daf-41b \mbox{}\protect\newline Daf-2b \mbox{}\protect\newline Pges-2b \mbox{}\protect\newline Gst-4\&msp-38b &
  13.6 \ensuremath{\pm} 0.3 \mbox{}\protect\newline \ensuremath{\uparrow}18.8\ensuremath{\pm}1.2 \mbox{}\protect\newline \ensuremath{\uparrow}17.1\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\uparrow}16.7\ensuremath{\pm}0.6 \mbox{}\protect\newline \ensuremath{\downarrow}13.4\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}12.9\ensuremath{\pm}0.4\\
17 &
  \unskip~\citep{735632:17464541} &
  25 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM-Ampicillin \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Hel-1(gk148684)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Osm-5(p813)b \mbox{}\protect\newline Hel-1;osm-5(p813)b \mbox{}\protect\newline Vhl-(ok161)b \mbox{}\protect\newline Hel-1;vhl-1(ok161)b \mbox{}\protect\newline Eat-2(ad1116)b \mbox{}\protect\newline Hel-1;eat-2b \mbox{}\protect\newline Isp-1(qm150)b \mbox{}\protect\newline Hel-1;isp-1b &
  16.9\ensuremath{\pm}0.6 \mbox{}\protect\newline \ensuremath{\uparrow}17.0\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}39.7\ensuremath{\pm}1.1 \mbox{}\protect\newline \ensuremath{\uparrow}27.0\ensuremath{\pm}0.9 \mbox{}\protect\newline \ensuremath{\uparrow}21.9\ensuremath{\pm}1.6 \mbox{}\protect\newline \ensuremath{\uparrow}22.9\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}23.8\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}23.0\ensuremath{\pm}0.6 \mbox{}\protect\newline \ensuremath{\uparrow}23.3\ensuremath{\pm}0.8 \mbox{}\protect\newline \ensuremath{\uparrow}23.8\ensuremath{\pm}0.9 \mbox{}\protect\newline \ensuremath{\uparrow}21.2\ensuremath{\pm}0.7\\
18 &
  \unskip~\citep{735632:17464542} &
  60 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM-Ampicillin \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-18(E1375)b \mbox{}\protect\newline Akt-1(Mg144)b \mbox{}\protect\newline Jnk-1(Gk7)b \mbox{}\protect\newline Jkk-1(Km2)b \mbox{}\protect\newline Pdk-1(Mg142)b \mbox{}\protect\newline Daf-16(mgDf50)b \mbox{}\protect\newline Glod-4(Gk189)b &
  22.78\ensuremath{\pm}0.23 \mbox{}\protect\newline \ensuremath{\downarrow}18.60\ensuremath{\pm}0.26 \mbox{}\protect\newline \ensuremath{\downarrow}18.55\ensuremath{\pm}0.26 \mbox{}\protect\newline \ensuremath{\uparrow}39.52\ensuremath{\pm}0.61 \mbox{}\protect\newline \ensuremath{\uparrow}33.38\ensuremath{\pm}0.43 \mbox{}\protect\newline \ensuremath{\uparrow}29.18\ensuremath{\pm}0.40 \mbox{}\protect\newline \ensuremath{\downarrow}17.80\ensuremath{\pm}0.25 \mbox{}\protect\newline No effect (22.78\ensuremath{\pm}0.23)\\
19 &
  \unskip~\citep{735632:17464484} &
  100 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Skn-1(zu67)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-2;skn-1b &
  23.4\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}16.9\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\uparrow}36.7\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\downarrow}17.1\ensuremath{\pm}0.2\\
20 &
  \unskip~\citep{735632:17464543} &
  20-30 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-16(mu86)b  \mbox{}\protect\newline Ins-7(ok1573)c &
  17.04\ensuremath{\pm}0.42 \mbox{}\protect\newline \ensuremath{\downarrow}15.72\ensuremath{\pm}0.26 \mbox{}\protect\newline \ensuremath{\uparrow}19.08\ensuremath{\pm}0.29 \\
21 &
  \unskip~\citep{735632:17464544} &
  100 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2b  \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Daf-16;daf-2b \mbox{}\protect\newline Nog-1b \mbox{}\protect\newline Nog-1;sir-2.1b \mbox{}\protect\newline Nog-1;daf-16b \mbox{}\protect\newline Sir-2.1(ok434)b \mbox{}\protect\newline Sir-2.1;daf-2b &
  12.21\ensuremath{\pm}0.24 \mbox{}\protect\newline \ensuremath{\uparrow}13.2\ensuremath{\pm}0.30 \mbox{}\protect\newline \ensuremath{\downarrow}12.9\ensuremath{\pm}0.25 \mbox{}\protect\newline \ensuremath{\downarrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\uparrow}12.29\ensuremath{\pm}0.27 \mbox{}\protect\newline \ensuremath{\downarrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\downarrow}(No numerical data)  \mbox{}\protect\newline \ensuremath{\downarrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\uparrow}(No numerical data) \\
22 &
  \unskip~\citep{735632:17464557} &
  25 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Ndg-4(lb108)b \mbox{}\protect\newline Ndg-4;lipl-4b \mbox{}\protect\newline Ndg-4;nhr-80b \mbox{}\protect\newline Ndg-4(sa529)b \mbox{}\protect\newline Ndg-4(lb108/sa529)b \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Daf-16;ndg-4b \mbox{}\protect\newline Aak-2(pk524)b \mbox{}\protect\newline Aak-2(ok524)b \mbox{}\protect\newline Aak-2;ndg-4b \mbox{}\protect\newline Ndg-4;daf-2b \mbox{}\protect\newline Daf-2b \mbox{}\protect\newline Nrf-5(sa513)b &
  17.0\ensuremath{\pm}1.0 \mbox{}\protect\newline \ensuremath{\uparrow}29.0\ensuremath{\pm}2.0 \mbox{}\protect\newline \ensuremath{\uparrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\downarrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\uparrow} (No numerical data)  \mbox{}\protect\newline \ensuremath{\uparrow} (No numerical data)  \mbox{}\protect\newline \ensuremath{\downarrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\downarrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\downarrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\downarrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\uparrow}20.9\ensuremath{\pm}2.9 \mbox{}\protect\newline \ensuremath{\uparrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\uparrow}(No numerical data) \mbox{}\protect\newline \ensuremath{\uparrow}(No numerical data) \\
\multicolumn{1}{p{\dimexpr(.08849999999999998\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{23}} &
  \multicolumn{1}{p{\dimexpr(.15309999999999997\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{\unskip~\citep{735632:17464572}}} &
  \multicolumn{1}{p{\dimexpr(.15540000000000001\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{40}} &
  20\ensuremath{^\circ}C \mbox{}\protect\newline E. coli HB101 \mbox{}\protect\newline NGM-streptomycin &
  N2a \mbox{}\protect\newline Tatn-1(baf1)b \mbox{}\protect\newline Eak-7(3188)b \mbox{}\protect\newline Eak-7;tatn-1b \mbox{}\protect\newline Aak-2(gt33)b \mbox{}\protect\newline Tatn-1;aak-2b &
  21.0 \mbox{}\protect\newline \ensuremath{\downarrow}23.0 \mbox{}\protect\newline \ensuremath{\uparrow}30.0 \mbox{}\protect\newline \ensuremath{\uparrow}33.5 \mbox{}\protect\newline \ensuremath{\downarrow}14.0 \mbox{}\protect\newline \ensuremath{\downarrow}13.0\\
 &
   &
   &
  20\ensuremath{^\circ}C \mbox{}\protect\newline E. coli HT115 \mbox{}\protect\newline NGM-streptomycin &
  N2a \mbox{}\protect\newline Tatn-1b \mbox{}\protect\newline Daf-2(e1368)b \mbox{}\protect\newline Tatn-1;daf-2b \mbox{}\protect\newline Daf-16(mgDf47)b \mbox{}\protect\newline Tatn-1;daf-16b &
  22.0 \mbox{}\protect\newline \ensuremath{\uparrow}24.0 \mbox{}\protect\newline \ensuremath{\uparrow}30.5 \mbox{}\protect\newline \ensuremath{\uparrow}37.0 \mbox{}\protect\newline \ensuremath{\downarrow}14.5 \mbox{}\protect\newline \ensuremath{\downarrow}17.0\\
\multicolumn{1}{p{\dimexpr(.08849999999999998\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{24}} &
  \multicolumn{1}{p{\dimexpr(.15309999999999997\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{\unskip~\citep{735632:17464566}}} &
  \multicolumn{1}{p{\dimexpr(.15540000000000001\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{60}} &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Daf-2(e1368)b \mbox{}\protect\newline Daf-12b \mbox{}\protect\newline Daf-12;daf-2b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-2;daf-12b \mbox{}\protect\newline Daf-36b \mbox{}\protect\newline Daf-36;daf-2b \mbox{}\protect\newline Daf-9b \mbox{}\protect\newline Daf-9;daf-2b &
  14.23\ensuremath{\pm}1.81 \mbox{}\protect\newline \ensuremath{\uparrow}28.24\ensuremath{\pm}5.39 \mbox{}\protect\newline \ensuremath{\downarrow}13.86\ensuremath{\pm}1.84 \mbox{}\protect\newline \ensuremath{\uparrow}25.26\ensuremath{\pm}3.95 \mbox{}\protect\newline \ensuremath{\uparrow}32.34\ensuremath{\pm}11.39 \mbox{}\protect\newline \ensuremath{\uparrow}31.77\ensuremath{\pm}9.86 \mbox{}\protect\newline \ensuremath{\downarrow}13.13\ensuremath{\pm}1.60 \mbox{}\protect\newline \ensuremath{\uparrow}22.84\ensuremath{\pm}4.94 \mbox{}\protect\newline \ensuremath{\downarrow}13.24\ensuremath{\pm}1.79 \mbox{}\protect\newline \ensuremath{\uparrow}24.96\ensuremath{\pm}4.67\\
 &
   &
   &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli HT1115 &
  N2a \mbox{}\protect\newline Daf-2(e1368)b \mbox{}\protect\newline Daf-12b \mbox{}\protect\newline Daf-12;daf-2b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-2;daf-12b \mbox{}\protect\newline Daf-36b \mbox{}\protect\newline Daf-36;daf-2b \mbox{}\protect\newline Daf-9b \mbox{}\protect\newline Daf-9;daf-2b &
  15.07\ensuremath{\pm}2.74 \mbox{}\protect\newline \ensuremath{\uparrow}24.93\ensuremath{\pm}4.37 \mbox{}\protect\newline \ensuremath{\downarrow}13.77\ensuremath{\pm}2.26 \mbox{}\protect\newline \ensuremath{\uparrow}24.61\ensuremath{\pm}5.81 \mbox{}\protect\newline \ensuremath{\uparrow}27.60\ensuremath{\pm}8.85 \mbox{}\protect\newline \ensuremath{\uparrow}25.23\ensuremath{\pm}9.17 \mbox{}\protect\newline \ensuremath{\downarrow}9.58\ensuremath{\pm}2.54 \mbox{}\protect\newline \ensuremath{\uparrow}23.70\ensuremath{\pm}5.45 \mbox{}\protect\newline \ensuremath{\downarrow}11.80\ensuremath{\pm}2.32 \mbox{}\protect\newline \ensuremath{\uparrow}23.99\ensuremath{\pm}5.52\\
25 &
  \unskip~\citep{735632:17464648} &
  60 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Eat-2(ad1116)b \mbox{}\protect\newline Aak-2(ok524)b \mbox{}\protect\newline Sir-2.1(ok434)c \mbox{}\protect\newline Par-4(it47)Vb &
  17.0 \mbox{}\protect\newline \ensuremath{\uparrow}65.0 \mbox{}\protect\newline \ensuremath{\uparrow}21.0 \mbox{}\protect\newline \ensuremath{\uparrow}31.0 \mbox{}\protect\newline \ensuremath{\uparrow}22.0 \mbox{}\protect\newline \ensuremath{\uparrow}28.0 \mbox{}\protect\newline \ensuremath{\uparrow}23.0\\
26 &
  \unskip~\citep{735632:17464580} &
  30 &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Daf-16 (mgDf50)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Age-1(hx546)b \mbox{}\protect\newline Osr-1(rm1)b \mbox{}\protect\newline Unc-43(n1186)b \mbox{}\protect\newline Sek-1(ag1)b \mbox{}\protect\newline Jnk-1(gk7)b \mbox{}\protect\newline Sir-2.1(ok434)c &
  11.83\ensuremath{\pm}0.94 \mbox{}\protect\newline \ensuremath{\downarrow}8.66\ensuremath{\pm}1.1 \mbox{}\protect\newline \ensuremath{\uparrow}26.66\ensuremath{\pm}1.7 \mbox{}\protect\newline \ensuremath{\uparrow}28.50\ensuremath{\pm}1.3 \mbox{}\protect\newline \ensuremath{\downarrow}10.50\ensuremath{\pm}0.8 \mbox{}\protect\newline \ensuremath{\uparrow}14.00\ensuremath{\pm}1.0 \mbox{}\protect\newline \ensuremath{\uparrow}12.50\ensuremath{\pm}1.0 \mbox{}\protect\newline \ensuremath{\downarrow}10.78\ensuremath{\pm}0.0 \mbox{}\protect\newline \ensuremath{\uparrow}13.00\ensuremath{\pm}1.9\\
27 &
  \unskip~\citep{735632:17464500} &
  50 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Asm-3(ok1744)b \mbox{}\protect\newline Asm-1b  \mbox{}\protect\newline Asm-2b  \mbox{}\protect\newline Asm-3;aap-1b \mbox{}\protect\newline Asm-3; age-1b \mbox{}\protect\newline Age-1(mg305)b \mbox{}\protect\newline Aap-1(m889)b &
  15.3\ensuremath{\pm}0.58 \mbox{}\protect\newline \ensuremath{\uparrow}14\% (17.4\ensuremath{\pm}0.69) \mbox{}\protect\newline \ensuremath{\uparrow}12\% (22.0\ensuremath{\pm}0.52) \mbox{}\protect\newline \ensuremath{\uparrow}10\% (21.6\ensuremath{\pm}0.57) \mbox{}\protect\newline \ensuremath{\uparrow}21\% (51.33\ensuremath{\pm}2.23) \mbox{}\protect\newline \ensuremath{\uparrow}67\% (69.6\ensuremath{\pm}1.52) \mbox{}\protect\newline \ensuremath{\uparrow}41.7\ensuremath{\pm}0.98 \mbox{}\protect\newline \ensuremath{\uparrow}42.41\ensuremath{\pm}1.79\\
28 &
  \unskip~\citep{735632:17464619} &
  100 &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Ins-18(tm339)c \mbox{}\protect\newline Ins-18(tm339)b \mbox{}\protect\newline Ins-18;ins-7(tm1907)b \mbox{}\protect\newline Ins-7(tm1907)b \mbox{}\protect\newline Daf-2;ins-18b \mbox{}\protect\newline Daf-2(e1370)b &
  17.0 \mbox{}\protect\newline \ensuremath{\uparrow}by 3.1 \mbox{}\protect\newline No numerical data \mbox{}\protect\newline \ensuremath{\downarrow}by 2.7 \mbox{}\protect\newline \ensuremath{\uparrow}by 4.8 \mbox{}\protect\newline \ensuremath{\downarrow}by 7.0 \mbox{}\protect\newline \ensuremath{\uparrow}46.0\\
29 &
  \unskip~\citep{735632:17464647} &
  60 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2(e1370)b Daf-16(mu86)b \mbox{}\protect\newline Tdp-1(ok803)b \mbox{}\protect\newline Daf-2;tdp-1b \mbox{}\protect\newline Daf-16;tdp-1b &
  16.0 \mbox{}\protect\newline \ensuremath{\uparrow}38.0 \mbox{}\protect\newline \ensuremath{\downarrow}13.0 \mbox{}\protect\newline \ensuremath{\uparrow}20.0 \mbox{}\protect\newline \ensuremath{\uparrow}33.0 \mbox{}\protect\newline \ensuremath{\downarrow}12.0\\
30 &
  \unskip~\citep{735632:17464578} &
  No data &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-16b \mbox{}\protect\newline Daf-2b \mbox{}\protect\newline Skn-1b &
  24.0 \mbox{}\protect\newline \ensuremath{\downarrow}21.0 \mbox{}\protect\newline \ensuremath{\uparrow}55.0 \mbox{}\protect\newline No effect (24.0)\\
31 &
  \unskip~\citep{735632:17464554} &
  20-30 &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Hsf-1(sy441)b \mbox{}\protect\newline Daf-7(e1372);hsf-1b \mbox{}\protect\newline Daf-7b &
  20.0 \mbox{}\protect\newline \ensuremath{\downarrow}13.0 \mbox{}\protect\newline No effect \mbox{}\protect\newline \ensuremath{\uparrow}23.0\\
\multicolumn{1}{p{\dimexpr(.08849999999999998\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{32}} &
  \multicolumn{1}{p{\dimexpr(.15309999999999997\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{\unskip~\citep{735632:17464582}}} &
  \multicolumn{1}{p{\dimexpr(.15540000000000001\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{45-60}} &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline Low-Density Feeding(LDF) \mbox{}\protect\newline E. coli OP50 \mbox{}\protect\newline (OD=0.18) &
  N2a \mbox{}\protect\newline Gpa-9(pk438)b \mbox{}\protect\newline Gpa-9XSc &
  19.56\ensuremath{\pm}0.62 \mbox{}\protect\newline No effect (19.56\ensuremath{\pm}0.62) \mbox{}\protect\newline \ensuremath{\uparrow}20.26\ensuremath{\pm}1.09\\
 &
   &
   &
  High Density Feeding \mbox{}\protect\newline (HDF) \mbox{}\protect\newline E. coli OP50 \mbox{}\protect\newline (OD=1.5) &
  N2a \mbox{}\protect\newline Gpa-9(pk438)b \mbox{}\protect\newline Gpa-9XSc &
  16.22\ensuremath{\pm}0.14 \mbox{}\protect\newline No effect (16.22\ensuremath{\pm}0.14) \mbox{}\protect\newline \ensuremath{\uparrow}20.08\ensuremath{\pm}0.18\\
33 &
  \unskip~\citep{735632:17464593} &
  100 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2b \mbox{}\protect\newline Sea-2(bp283)b \mbox{}\protect\newline Sea-2;daf-2b \mbox{}\protect\newline Daf-16;sea-2;daf-2b &
  17.3\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}29.1\ensuremath{\pm}1.4 \mbox{}\protect\newline \ensuremath{\uparrow}20.1\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}36.7\ensuremath{\pm}1.7 \mbox{}\protect\newline \ensuremath{\downarrow}13.1\ensuremath{\pm}0.5\\
34 &
  \unskip~\citep{735632:17464563} &
  100 &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Ins-6(tm2416)b \mbox{}\protect\newline Daf-28(tm2308)b \mbox{}\protect\newline Ins-1(nr2091)b \mbox{}\protect\newline Ins-6;daf-28b  &
  13.0\ensuremath{\pm}0.1 \mbox{}\protect\newline \ensuremath{\uparrow}14.5\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\uparrow}13.9\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\downarrow}12.6\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\uparrow}13.9\ensuremath{\pm}0.4\\
35 &
  \unskip~\citep{735632:17464606} &
  25-50 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Atx-3(gk193)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Cdc-48.2(tm659)b \mbox{}\protect\newline Cdc-48.2;atx-3b \mbox{}\protect\newline Cdc-48.1(tm544)b \mbox{}\protect\newline Cdc-48.1;atx-3b \mbox{}\protect\newline Cdc-48.1;daf-2;atx-3b \mbox{}\protect\newline Daf-16b \mbox{}\protect\newline Cdc-48.1;atx-3;daf-16b \mbox{}\protect\newline Pha-4b \mbox{}\protect\newline Cdc-48.1;atx-3;pha-4b &
  26.0 \mbox{}\protect\newline \ensuremath{\uparrow}30.0 \mbox{}\protect\newline \ensuremath{\uparrow}40.0 \mbox{}\protect\newline \ensuremath{\uparrow}28.0 \mbox{}\protect\newline \ensuremath{\uparrow}28.0 \mbox{}\protect\newline \ensuremath{\uparrow}30.0 \mbox{}\protect\newline \ensuremath{\uparrow}43.0 \mbox{}\protect\newline \ensuremath{\uparrow}40.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\downarrow}18.0 \mbox{}\protect\newline \ensuremath{\uparrow}27.0 \mbox{}\protect\newline \ensuremath{\uparrow}35.0\\
36 &
  \unskip~\citep{735632:17464655} &
  100 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Age-1(hx546)b \mbox{}\protect\newline Daf-16(mgdf50)b &
  31.5\ensuremath{\pm}6.4 \mbox{}\protect\newline \ensuremath{\uparrow}47.1\ensuremath{\pm}15.1 \mbox{}\protect\newline \ensuremath{\downarrow}19.2\ensuremath{\pm}2.8\\
37 &
  \unskip~\citep{735632:17464584} &
  46 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Ire-1(ok799);daf-2b \mbox{}\protect\newline Daf-2(e1368)b \mbox{}\protect\newline Daf-2;xbp-1b \mbox{}\protect\newline Ire-1(ok799);daf-2b \mbox{}\protect\newline Ire-1(ok799)b \mbox{}\protect\newline Daf-2;xbp-1b \mbox{}\protect\newline Xbp-1(zc12)b &
  16.5 \mbox{}\protect\newline \ensuremath{\uparrow}42.0 \mbox{}\protect\newline \ensuremath{\uparrow}19.9 \mbox{}\protect\newline \ensuremath{\uparrow}32.8 \mbox{}\protect\newline \ensuremath{\uparrow}23.6 \mbox{}\protect\newline \ensuremath{\downarrow}16.0 \mbox{}\protect\newline \ensuremath{\downarrow}13.2 \mbox{}\protect\newline \ensuremath{\uparrow}36.6 \mbox{}\protect\newline \ensuremath{\downarrow}16.2\\
38 &
  \unskip~\citep{735632:17464583} &
  15 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Eat-2(ad1116)b \mbox{}\protect\newline Daf-16(mgDf50)b &
  34.0 \mbox{}\protect\newline \ensuremath{\uparrow}44.0 \mbox{}\protect\newline \ensuremath{\downarrow}24.0\\
39 &
  \unskip~\citep{735632:17464642} &
  60 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Ets-4(ok165)b \mbox{}\protect\newline Ets-4(uz1)b \mbox{}\protect\newline Daf-2b &
  13.36\ensuremath{\pm}0.6 \mbox{}\protect\newline \ensuremath{\uparrow}18.0\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}18.2\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}22.4\ensuremath{\pm}1.4\\
40 &
  \unskip~\citep{735632:17464637} &
  30 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Ttx-3(ks5)b \mbox{}\protect\newline Sra-11(ok630)b \mbox{}\protect\newline Ceh-10(ct78)b \mbox{}\protect\newline Ceh-23(ms23)b &
  13.1\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}10.7\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}30.6\ensuremath{\pm}1.6 \mbox{}\protect\newline \ensuremath{\downarrow}11.8\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}13.0\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\downarrow}7.9\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\downarrow}12.8\ensuremath{\pm}0.4\\
41 &
  \unskip~\citep{735632:17464638} &
  30 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Odr-7(ky4)b \mbox{}\protect\newline Odr-2(n2145)b \mbox{}\protect\newline Odr-3(n2150)b &
  13.1\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}10.7\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}30.6\ensuremath{\pm}1.6 \mbox{}\protect\newline \ensuremath{\uparrow}16.6\ensuremath{\pm}0.6 \mbox{}\protect\newline \ensuremath{\uparrow}16.3\ensuremath{\pm}0.6 \mbox{}\protect\newline \ensuremath{\uparrow}16.6\ensuremath{\pm}0.6\\
42 &
  \unskip~\citep{735632:17464562} &
  60 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Tir-1b \mbox{}\protect\newline Daf-16b  &
  24.0 \mbox{}\protect\newline \ensuremath{\uparrow}18\% \mbox{}\protect\newline \ensuremath{\downarrow}25\%\\
43 &
  \unskip~\citep{735632:17464581} &
  100 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Gpa-3(pk35)b \mbox{}\protect\newline Gpa-3(syIs25)b \mbox{}\protect\newline Daf-11(m47)b &
  22.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\uparrow}35.0 \mbox{}\protect\newline \ensuremath{\uparrow}25.0\\
44 &
  \unskip~\citep{735632:17464595} &
  No data &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Ced-3(n717)b \mbox{}\protect\newline Daf-2b  &
  16.5 \mbox{}\protect\newline \ensuremath{\downarrow}15.6 \mbox{}\protect\newline \ensuremath{\uparrow}30.1\\
45 &
  \unskip~\citep{735632:17464658} &
  10 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline liquid  \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Eat-2(ad1113)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-16(m26)b &
  20.84\ensuremath{\pm}4.71  \mbox{}\protect\newline \ensuremath{\uparrow}25.90\ensuremath{\pm}4.51 \mbox{}\protect\newline \ensuremath{\uparrow}48.36\ensuremath{\pm}12.70 \mbox{}\protect\newline \ensuremath{\downarrow}12.84\ensuremath{\pm}2.11\\
\multicolumn{1}{p{\dimexpr(.08849999999999998\linewidth-2\tabcolsep)}}{\multirow{13}{\linewidth}{46}} &
  \multicolumn{1}{p{\dimexpr(.15309999999999997\linewidth-2\tabcolsep)}}{\multirow{13}{\linewidth}{\unskip~\citep{735632:17464533}}} &
  101 &
  \multicolumn{1}{p{\dimexpr(.13\linewidth-2\tabcolsep)}}{\multirow{13}{\linewidth}{20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50}} &
  N2a &
  12.7\ensuremath{\pm}2.1\\
 &
   &
  103 &
   &
  Daf-2(e1370)b &
  \ensuremath{\uparrow}23.5\ensuremath{\pm}2.7\\
 &
   &
  \multicolumn{1}{p{\dimexpr(.15540000000000001\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{105 \mbox{}\protect\newline 105}} &
   &
  Akt-1(mg306)b &
  \ensuremath{\uparrow}13.7\ensuremath{\pm}2.6\\
 &
   &
   &
   &
  Eak-3(mg344)b &
  \ensuremath{\downarrow}12.6\ensuremath{\pm}2.6\\
 &
   &
  97 &
   &
  Eak-4(mg348)b &
  \ensuremath{\uparrow}12.9\ensuremath{\pm}1.9\\
 &
   &
  102 &
   &
  Sdf-9(ut187)b &
  \ensuremath{\uparrow}12.9\ensuremath{\pm}2.0\\
 &
   &
  101 &
   &
  Sdf-9(mg337)b &
  \ensuremath{\uparrow}12.9\ensuremath{\pm}1.9\\
 &
   &
  100 &
   &
  Eak-6(mg329)b &
  \ensuremath{\uparrow}12.9\ensuremath{\pm}1.6\\
 &
   &
  99 &
   &
  Eak-3;akt-1 &
  \ensuremath{\uparrow}13.0\ensuremath{\pm}2.1\\
 &
   &
  101 &
   &
  Eak-4;akt-1 &
  \ensuremath{\uparrow}13.1\ensuremath{\pm}2.2\\
 &
   &
  99 &
   &
  Akt-1;sdf-9(ut187) &
  \ensuremath{\uparrow}12.7\ensuremath{\pm}2.5\\
 &
   &
  101 &
   &
  Akt-1;sdf-9(mg337) &
  \ensuremath{\uparrow}13.0\ensuremath{\pm}2.5\\
 &
   &
  97 &
   &
  Eak-6;akt-1 &
  \ensuremath{\uparrow}12.8\ensuremath{\pm}2.1\\
47 &
  \unskip~\citep{735632:17464529} &
  100 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Age-1(hx546)b \mbox{}\protect\newline Daf-16(mgDf50)b \mbox{}\protect\newline Mev-1(kn1)b &
  32.1\ensuremath{\pm}4.2 \mbox{}\protect\newline \ensuremath{\uparrow}37.4\ensuremath{\pm}5.5 \mbox{}\protect\newline \ensuremath{\downarrow}18.6\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\downarrow}21.8\ensuremath{\pm}2.1\\
\multicolumn{1}{p{\dimexpr(.08849999999999998\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{48}} &
  \multicolumn{1}{p{\dimexpr(.15309999999999997\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{\unskip~\citep{735632:17464530}}} &
  \multicolumn{1}{p{\dimexpr(.15540000000000001\linewidth-2\tabcolsep)}}{\multirow{2}{\linewidth}{30}} &
  25\ensuremath{^\circ}C \mbox{}\protect\newline Liquid \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Pcm-1(qa201)b \mbox{}\protect\newline Daf-2(m41)b \mbox{}\protect\newline Daf-7(e1372)b \mbox{}\protect\newline Daf-2(m41); pcm-1b  &
  15.0 \mbox{}\protect\newline \ensuremath{\uparrow}17\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}24\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow} (No numerical data)  \mbox{}\protect\newline \ensuremath{\uparrow} (No numerical data) \\
 &
   &
   &
  20\ensuremath{^\circ}C \mbox{}\protect\newline Liquid \mbox{}\protect\newline E. coli OP50 &
  N2a  \mbox{}\protect\newline Pcm-1(qa201)b \mbox{}\protect\newline Daf-2(m41)b \mbox{}\protect\newline Daf-7(e1372)b \mbox{}\protect\newline Daf-2(m41); pcm-1b &
  30.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\uparrow}58.0 \mbox{}\protect\newline \ensuremath{\uparrow}60.0 \mbox{}\protect\newline \ensuremath{\uparrow}60.0\\
49 &
  \unskip~\citep{735632:17464531} &
  No data &
  15\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline \textit{E. coli} OP50 &
  N2\ensuremath{^{a}} \mbox{}\protect\newline Sod-2(sj173)\ensuremath{^{b}} \mbox{}\protect\newline Sod-3(sj134)\ensuremath{^{b}} \mbox{}\protect\newline Sod-2;sod-3\ensuremath{^{b}} \mbox{}\protect\newline Daf-2(e1370)\ensuremath{^{b}} \mbox{}\protect\newline Sod-2;daf-2\ensuremath{^{b}} \mbox{}\protect\newline Daf-2;sod-3\ensuremath{^{b}} &
  22.7\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\downarrow}22.5\ensuremath{\pm}1.4 \mbox{}\protect\newline \ensuremath{\downarrow}21.5\ensuremath{\pm}1.1 \mbox{}\protect\newline \ensuremath{\downarrow}20.4\ensuremath{\pm}2.3 \mbox{}\protect\newline \ensuremath{\uparrow}45.7\ensuremath{\pm}4.7 \mbox{}\protect\newline \ensuremath{\uparrow}41.0\ensuremath{\pm}7.2 \mbox{}\protect\newline \ensuremath{\uparrow}57.3\ensuremath{\pm}4.5\\
\tblbottomrule 
\end{longtable}
\endgroup
\makeatletter\@ifundefined{TwoColDocument}{}{\twocolumn}\makeatother 

\begin{table*}[!htbp]
\caption{\boldmath {(\textit{Continue from Table 2}) Effect of differential genes expression on the mean lifespan of\textit{ C. elegans}} }
\label{tw-1f2f4ec88855}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.14969999999999999\linewidth-2\tabcolsep}p{\dimexpr.1116\linewidth-2\tabcolsep}p{\dimexpr.0872\linewidth-2\tabcolsep}p{\dimexpr.2188\linewidth-2\tabcolsep}p{\dimexpr.2085\linewidth-2\tabcolsep}p{\dimexpr.2242\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}No. & Author & No. of worms used & Culture conditions & Gene tested & Lifespan (days)\\
\tblmidrule 
49(Continue) &
  \unskip~\citep{735632:17464531} &
  No data &
  15\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline \textit{E. coli} OP50 &
  Daf-2;sod-3\ensuremath{^{c}} \mbox{}\protect\newline Daf-2;mev-1\ensuremath{^{b}} \mbox{}\protect\newline Daf-7;sod-3\ensuremath{^{b}} \mbox{}\protect\newline Sod-2;daf-7;sod-3\ensuremath{^{b}} \mbox{}\protect\newline Sod-4(gk101)\ensuremath{^{b}} \mbox{}\protect\newline Daf-2;sod-4\ensuremath{^{b}} \mbox{}\protect\newline Sod-2;daf-7(e1372) \mbox{}\protect\newline Daf-7(e1372) \mbox{}\protect\newline Mev-1(kn-1) &
  \ensuremath{\uparrow}56.3\ensuremath{\pm}2.3 \mbox{}\protect\newline \ensuremath{\uparrow}46.1\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\uparrow}23.2\ensuremath{\pm}3.9 \mbox{}\protect\newline \ensuremath{\downarrow}22.1\ensuremath{\pm}2.0 \mbox{}\protect\newline \ensuremath{\downarrow}21.9\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\uparrow}63.7\ensuremath{\pm}7.3 \mbox{}\protect\newline \ensuremath{\uparrow}23.2 \mbox{}\protect\newline \ensuremath{\uparrow}24.3 \mbox{}\protect\newline \ensuremath{\downarrow}17.9\\
50 &
  \unskip~\citep{735632:17464574} &
  50 &
  12\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-16(m27)b \mbox{}\protect\newline Clk-1(e2519)b \mbox{}\protect\newline Eat-2(ad465)b \mbox{}\protect\newline Daf-2(e1370)b &
  33.7\ensuremath{\pm}6.4 \mbox{}\protect\newline \ensuremath{\downarrow}29.9\ensuremath{\pm}8.0 \mbox{}\protect\newline \ensuremath{\uparrow}40.7\ensuremath{\pm}8.4 \mbox{}\protect\newline \ensuremath{\uparrow}36.6\ensuremath{\pm}12.6 \mbox{}\protect\newline \ensuremath{\uparrow}38.9\ensuremath{\pm}12.3\\
 &
   &
   &
  18.5\ensuremath{^\circ}C  \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-16(m27)b \mbox{}\protect\newline Clk-1(e2519)b \mbox{}\protect\newline Eat-2(ad465)b \mbox{}\protect\newline Daf-2(e1370)b &
  19.2\ensuremath{\pm}4.7 \mbox{}\protect\newline \ensuremath{\downarrow}18.6\ensuremath{\pm}5.3 \mbox{}\protect\newline No numerical data \mbox{}\protect\newline No numerical data \mbox{}\protect\newline No numerical data \\
 &
   &
   &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-16(m27)b \mbox{}\protect\newline Clk-1(e2519)b \mbox{}\protect\newline Eat-2(ad465)b \mbox{}\protect\newline Daf-2(e1370)b &
  12.6\ensuremath{\pm}3.0 \mbox{}\protect\newline \ensuremath{\downarrow}9.5\ensuremath{\pm}1.3 \mbox{}\protect\newline \ensuremath{\uparrow}18.7\ensuremath{\pm}4.3 \mbox{}\protect\newline \ensuremath{\uparrow}17.3\ensuremath{\pm}4.7 \mbox{}\protect\newline \ensuremath{\uparrow}38.7\ensuremath{\pm}15.2\\
51 &
  \unskip~\citep{735632:17464576} &
  90 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-2(mu150)b \mbox{}\protect\newline Daf-2(e1368)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Glp-1(e2141ts)b \mbox{}\protect\newline Eat-2(ad1116)b &
  20.7\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}33.4\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}32.7\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}40.8\ensuremath{\pm}1.0 \mbox{}\protect\newline \ensuremath{\uparrow}23.2\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}27.3\ensuremath{\pm}0.6 \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Effect of differential genes expression on the mean and maximum lifespan of\textit{ C. elegans}} }
\label{tw-b9eb2520c33b}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0668\linewidth-2\tabcolsep}p{\dimexpr.0877\linewidth-2\tabcolsep}p{\dimexpr.10530000000000001\linewidth-2\tabcolsep}p{\dimexpr.143\linewidth-2\tabcolsep}p{\dimexpr.24179999999999996\linewidth-2\tabcolsep}p{\dimexpr.1746\linewidth-2\tabcolsep}p{\dimexpr.1808\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}No.  & Author  & No. of worms used \mbox{}\protect\newline  & Culture conditions  & Gene tested  & \multicolumn{2}{p{\dimexpr(.3554\linewidth-2\tabcolsep)}}{\cAlignHack Lifespan (days) \mbox{}\protect\newline }\\
\rowcolor{kwdboxcolor} &  &  &  &  & Mean & Maximum\\
\tblmidrule 
1 &
  \unskip~\citep{735632:17464549} &
  No data  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Ftt-1b \mbox{}\protect\newline Ftt-2b \mbox{}\protect\newline Daf-16(mgDf50)b \mbox{}\protect\newline Daf-16;ftt-1b  \mbox{}\protect\newline Daf-16;ftt-2b \mbox{}\protect\newline Daf-2(e1365)b \mbox{}\protect\newline Daf-2;ftt-1b \mbox{}\protect\newline Daf-2;ftt-2b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-2;ftt-1b \mbox{}\protect\newline Daf-2;ftt-2b \mbox{}\protect\newline Pdk-1(sa709)b \mbox{}\protect\newline Pdk-1;ftt-1b \mbox{}\protect\newline Pdk-1;ftt-2b \mbox{}\protect\newline Pdk-1(mg142)b \mbox{}\protect\newline Pdk-1;ftt-1b \mbox{}\protect\newline Pdk-1;ftt-2b  &
  18.9\ensuremath{\pm}0.1 \mbox{}\protect\newline \ensuremath{\downarrow}16.4\ensuremath{\pm}0.1 \mbox{}\protect\newline \ensuremath{\downarrow}15.6\ensuremath{\pm}0.1 \mbox{}\protect\newline \ensuremath{\downarrow}13.9\ensuremath{\pm}0.1 \mbox{}\protect\newline \ensuremath{\downarrow}14.0\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}12.8\ensuremath{\pm}0.1 \mbox{}\protect\newline \ensuremath{\uparrow}31.3\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}25.4\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\uparrow}23.4\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}28.6\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}19.6\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\downarrow}18.5\ensuremath{\pm}0.1 \mbox{}\protect\newline \ensuremath{\uparrow}21.5\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\uparrow}24.7\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}21.5\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}19.1\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\uparrow}19.5\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\downarrow}17.6\ensuremath{\pm}0.2  &
  28.0 \mbox{}\protect\newline \ensuremath{\uparrow}29.0 \mbox{}\protect\newline \ensuremath{\uparrow}31.0 \mbox{}\protect\newline \ensuremath{\downarrow}24.0 \mbox{}\protect\newline \ensuremath{\uparrow}29.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\uparrow}42.0 \mbox{}\protect\newline \ensuremath{\uparrow}38.0 \mbox{}\protect\newline \ensuremath{\uparrow}38.0 \mbox{}\protect\newline \ensuremath{\uparrow}44.0 \mbox{}\protect\newline \ensuremath{\uparrow}39.0 \mbox{}\protect\newline \ensuremath{\uparrow}39.0 \mbox{}\protect\newline \ensuremath{\uparrow}42.0 \mbox{}\protect\newline \ensuremath{\uparrow}45.0 \mbox{}\protect\newline \ensuremath{\uparrow}43.0 \mbox{}\protect\newline \ensuremath{\downarrow}26.0 \mbox{}\protect\newline 28.0 \mbox{}\protect\newline \ensuremath{\uparrow}31.0 \\
\multicolumn{1}{p{\dimexpr(.0668\linewidth-2\tabcolsep)}}{\multirow{6}{\linewidth}{2}} &
  \multicolumn{1}{p{\dimexpr(.0877\linewidth-2\tabcolsep)}}{\multirow{6}{\linewidth}{\unskip~\citep{735632:17464571}}} &
  124  &
  \multicolumn{1}{p{\dimexpr(.143\linewidth-2\tabcolsep)}}{\multirow{6}{\linewidth}{20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50}} &
  N2a  &
  20.0 &
  35.0\\
 &
   &
  122  &
   &
  Fgt-1b  &
  \ensuremath{\uparrow}25.0 &
  \ensuremath{\uparrow}43.0\\
 &
   &
  126  &
   &
  Daf-2(e1370)b  &
  \ensuremath{\uparrow}26.0 &
  \ensuremath{\uparrow}41.0\\
 &
   &
  121  &
   &
  Age-1(hx546)b  &
  No data &
  \ensuremath{\uparrow}41.0\\
 &
   &
  123  &
   &
  Fgt-1;daf-2b  &
  \ensuremath{\uparrow}29.0 &
  \ensuremath{\uparrow}47.0\\
 &
   &
  116  &
   &
  Fgt-1;age-1b  &
  \ensuremath{\uparrow}27.0 &
  \ensuremath{\uparrow}44.0\\
3  &
  \unskip~\citep{735632:17464602} &
  60  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM-Ampicillin \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Age-1(hx546)b \mbox{}\protect\newline Age-1;rme-1b \mbox{}\protect\newline Age-1;rme-6b \mbox{}\protect\newline Age-1;rme-8b \mbox{}\protect\newline Clk-1(e2519)b \mbox{}\protect\newline Clk-1;rme-1b \mbox{}\protect\newline Eat-2(ad465)b \mbox{}\protect\newline Eat-2;rme-1b \mbox{}\protect\newline Eat-2;rme6b \mbox{}\protect\newline Eat-2;rme-8b \mbox{}\protect\newline Rme-1b  &
  16.3 \mbox{}\protect\newline \ensuremath{\uparrow}20.8 \mbox{}\protect\newline \ensuremath{\downarrow}13.1 \mbox{}\protect\newline \ensuremath{\uparrow}19.8 \mbox{}\protect\newline \ensuremath{\uparrow}19.1 \mbox{}\protect\newline \ensuremath{\uparrow}17.9 \mbox{}\protect\newline \ensuremath{\uparrow}18.3 \mbox{}\protect\newline \ensuremath{\uparrow}18.2 \mbox{}\protect\newline \ensuremath{\uparrow}18.4 \mbox{}\protect\newline \ensuremath{\uparrow}18.4 \mbox{}\protect\newline \ensuremath{\uparrow}19.8 \mbox{}\protect\newline \ensuremath{\uparrow}17.6  &
  27.0 \mbox{}\protect\newline \ensuremath{\uparrow}33.0 \mbox{}\protect\newline \ensuremath{\downarrow}25.0 \mbox{}\protect\newline \ensuremath{\uparrow}28.0  \mbox{}\protect\newline \ensuremath{\uparrow}32.0 \mbox{}\protect\newline \ensuremath{\uparrow}29.0 \mbox{}\protect\newline \ensuremath{\uparrow}30.0 \mbox{}\protect\newline \ensuremath{\uparrow}30.0  \mbox{}\protect\newline \ensuremath{\downarrow}24.0 \mbox{}\protect\newline \ensuremath{\downarrow}24.0 \mbox{}\protect\newline \ensuremath{\uparrow}30.0 \mbox{}\protect\newline \ensuremath{\uparrow}28.0 \\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{*NGM = Nematode Growth Medium}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{ThreePartTable}

\centering 
\begingroup
\makeatletter\if@twocolumn\@ifundefined{theposttbl}{\gdef\TwoColDocument{true}\onecolumn\onecolumn}{}\fi\makeatother 
\begin{TableNotes}\footnotesize 
    
\item{*NGM = Nematode Growth Medium}
\end{TableNotes}\setlength\LTcapwidth{\textwidth}
\begin{longtable}{p{\dimexpr.0723\linewidth-2\tabcolsep}p{\dimexpr.1277\linewidth-2\tabcolsep}p{\dimexpr.1173\linewidth-2\tabcolsep}p{\dimexpr.14389999999999995\linewidth-2\tabcolsep}p{\dimexpr.2684\linewidth-2\tabcolsep}p{\dimexpr.2704\linewidth-2\tabcolsep}}
\caption{\boldmath {Effect of differential genes expression on the maximum lifespan of \textit{C. ele }} }
\label{tw-e07c50bb4638}
\def\arraystretch{1.1}\\\endfirsthead \hline \noalign{\vskip3pt} \noalign{\textit{Table \thetable\ continued}} \noalign{\vskip3pt} 
\tbltoprule \rowcolor{kwdboxcolor}No.  & Author  & No. of worms used & Culture conditions  & Gene tested  & Lifespan (days)\\
\tblmidrule \endhead \hline \noalign{\vskip3pt} \noalign{\textit{\hfill Continued on next page}} \noalign{\vskip3pt} \endfoot \insertTableNotes \endlastfoot 
\tbltoprule \rowcolor{kwdboxcolor}No.  & Author  & No. of worms used & Culture conditions  & Gene tested  & Lifespan (days)\\
\tblmidrule 
1 &
  \unskip~\citep{735632:17464609} &
  36  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Daf-16b \mbox{}\protect\newline Hsf-1b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-2(e1368)b \mbox{}\protect\newline Aqp-1b  &
  32.0 \mbox{}\protect\newline \ensuremath{\downarrow}22.0 \mbox{}\protect\newline \ensuremath{\downarrow}15.0 \mbox{}\protect\newline \ensuremath{\uparrow}80.0 \mbox{}\protect\newline \ensuremath{\uparrow}45.0 \mbox{}\protect\newline \ensuremath{\downarrow}30.0 \\
2 &
  \unskip~\citep{735632:17464587} &
  No data  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Daf-2b \mbox{}\protect\newline Sod-2; daf-2b \mbox{}\protect\newline Sod-2; daf-2; Ex[sod-2]c \mbox{}\protect\newline Daf-2; sod-3b \mbox{}\protect\newline Daf-2; sod-3; Ex[sod-3]c  &
  30.0 \mbox{}\protect\newline \ensuremath{\uparrow}75.0 \mbox{}\protect\newline \ensuremath{\uparrow}65.0 \mbox{}\protect\newline \ensuremath{\uparrow}100.0 \mbox{}\protect\newline \ensuremath{\uparrow}100.0 \mbox{}\protect\newline \ensuremath{\uparrow}75.0\\
3 &
  \unskip~\citep{735632:17464601} &
  No data  &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Transgenic strains:  \mbox{}\protect\newline PL51c  &
  17.0 \mbox{}\protect\newline \ensuremath{\uparrow}25\% (25.0) \\
4 &
  \unskip~\citep{735632:17464610} &
  40  &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli HB101  &
  N2a \mbox{}\protect\newline Pash-1tsb  &
  15.0 \mbox{}\protect\newline \ensuremath{\downarrow}10.0\\
5 &
  \unskip~\citep{735632:17464540} &
  30 &
  20 \ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Hsf-1(sy441)b \mbox{}\protect\newline Rsks-1(tm1714)b \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Daf-2(e1370)b &
  30.0 \mbox{}\protect\newline \ensuremath{\downarrow}25.0 \mbox{}\protect\newline \ensuremath{\uparrow}40.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\uparrow}58.0\\
6 &
  \unskip~\citep{735632:17464596} &
  25 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline Liquid \mbox{}\protect\newline E. coli HT115 &
  N2a \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-2;mxl-1(tm1530)b \mbox{}\protect\newline Daf-2;mxl-2(tm1516)b \mbox{}\protect\newline Daf-3(tm4940)b \mbox{}\protect\newline Eat-2(ad465)b \mbox{}\protect\newline Eat-2;mxl-1b \mbox{}\protect\newline Eat-2;mxl-2b \mbox{}\protect\newline Mdl-1(tm311)b \mbox{}\protect\newline Mml-1(ok849)b \mbox{}\protect\newline Mxl-1(tm1530)b \mbox{}\protect\newline Mxl-2(tm1516)b \mbox{}\protect\newline Mxl-3(ok1947)b \mbox{}\protect\newline Daf-16(mgDf47)b &
  25.1\ensuremath{\pm}0.9 \mbox{}\protect\newline \ensuremath{\uparrow}60.5\ensuremath{\pm}2.4 \mbox{}\protect\newline \ensuremath{\uparrow}83.9\ensuremath{\pm}3.3 \mbox{}\protect\newline \ensuremath{\uparrow}43.2\ensuremath{\pm}3.3 \mbox{}\protect\newline \ensuremath{\downarrow}22.0\ensuremath{\pm}1.9 \mbox{}\protect\newline \ensuremath{\uparrow}44.1\ensuremath{\pm}2.6 \mbox{}\protect\newline \ensuremath{\uparrow}40.1\ensuremath{\pm}2.7 \mbox{}\protect\newline \ensuremath{\downarrow}23.1\ensuremath{\pm}1.1 \mbox{}\protect\newline \ensuremath{\uparrow}40.3\ensuremath{\pm}3.2 \mbox{}\protect\newline \ensuremath{\downarrow}22.4\ensuremath{\pm}1.5 \mbox{}\protect\newline \ensuremath{\uparrow}35.7\ensuremath{\pm}1.5 \mbox{}\protect\newline \ensuremath{\downarrow}21.2\ensuremath{\pm}1.3 \mbox{}\protect\newline \ensuremath{\uparrow}41.6\ensuremath{\pm}3.7 \mbox{}\protect\newline \ensuremath{\downarrow}22.8\ensuremath{\pm}2.4\\
7 &
  \unskip~\citep{735632:17464639} &
  No data &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline \textit{E. coli} OP50 &
  N2\ensuremath{^{a}} \mbox{}\protect\newline Daf-16\ensuremath{^{b}} \mbox{}\protect\newline Pha-4\ensuremath{^{b}} \mbox{}\protect\newline Zfp-1(ok554)\ensuremath{^{b}} \mbox{}\protect\newline Gfl-1\ensuremath{^{b}} &
  32.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\downarrow}28.0 \mbox{}\protect\newline \ensuremath{\downarrow}30.0 \mbox{}\protect\newline \ensuremath{\downarrow}28.0\\
\tblbottomrule 
\end{longtable}
\endgroup
\end{ThreePartTable}

\makeatletter\@ifundefined{TwoColDocument}{}{\twocolumn}\makeatother 

\begin{table*}[!htbp]
\caption{\boldmath {(\textit{Continue from Table 5}) Effect of differential genes expression on the maximum lifespan of \textit{C. elegans }} }
\label{tw-cc6c28da7127}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0677\linewidth-2\tabcolsep}p{\dimexpr.1796\linewidth-2\tabcolsep}p{\dimexpr.1831\linewidth-2\tabcolsep}p{\dimexpr.16580000000000002\linewidth-2\tabcolsep}p{\dimexpr.2165\linewidth-2\tabcolsep}p{\dimexpr.1873\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}No. & Author & No. of worms used & Culture conditions & Gene tested & Lifespan (days)\\
\tblmidrule 
8 &
  \unskip~\citep{735632:17464614} &
  100 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Pcrg-1(tm2597)b \mbox{}\protect\newline Daf-16b \mbox{}\protect\newline Pcrg-1;daf-16b \mbox{}\protect\newline Daf-2b \mbox{}\protect\newline Pcrg-1;daf-2b \mbox{}\protect\newline Eat-2b \mbox{}\protect\newline Pcrg-1;eat-2b &
  30.0 \mbox{}\protect\newline \ensuremath{\uparrow}28.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline No effect  \mbox{}\protect\newline \ensuremath{\uparrow}55.0 \mbox{}\protect\newline \ensuremath{\uparrow}60.0 \mbox{}\protect\newline \ensuremath{\uparrow}50.0 \mbox{}\protect\newline No effect\\
9 &
  \unskip~\citep{735632:17464611} &
  100 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Scav-3(qx193)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-2;scav-3b \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Daf-16;daf-2b \mbox{}\protect\newline Daf-16;daf-2;scav-3b \mbox{}\protect\newline Scav-3(ok1286)b \mbox{}\protect\newline Scav-3(tm3659)b  &
  30.0 \mbox{}\protect\newline \ensuremath{\downarrow}22.0 \mbox{}\protect\newline \ensuremath{\uparrow}73.0 \mbox{}\protect\newline \ensuremath{\uparrow}63.0 \mbox{}\protect\newline \ensuremath{\downarrow}25.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\downarrow}25.0 \mbox{}\protect\newline No effect\\
10 &
  \unskip~\citep{735632:17464652} &
  50-100 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Age-1(hx546)b  \mbox{}\protect\newline Daf-16bkob  &
  30.0 \mbox{}\protect\newline \ensuremath{\downarrow}28.0 \mbox{}\protect\newline \ensuremath{\downarrow}26.0 \mbox{}\protect\newline \ensuremath{\uparrow}34.0 \mbox{}\protect\newline \ensuremath{\downarrow}23.0\\
11 &
  \unskip~\citep{735632:17464631} &
  20 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline  *NGM \& liquid \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Daf-2(e1370)b  &
  15 days on solid media  \mbox{}\protect\newline 15 days on liquid media \mbox{}\protect\newline \ensuremath{\uparrow}42 days on liquid media \mbox{}\protect\newline \ensuremath{\uparrow}40 days on solid media\\
12 &
  \unskip~\citep{735632:17464616} &
  50 &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM-nystatin \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Age-1(hx546)b  &
  24.0 \mbox{}\protect\newline \ensuremath{\uparrow}40.0\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{*NGM= Nematode Growth Medium}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Effect of differential genes expression on the mean and median lifespan of \textit{C. elegans}} }
\label{tw-2c4b854faa9f}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0658\linewidth-2\tabcolsep}p{\dimexpr.11830000000000002\linewidth-2\tabcolsep}p{\dimexpr.08549999999999999\linewidth-2\tabcolsep}p{\dimexpr.10940000000000001\linewidth-2\tabcolsep}p{\dimexpr.2715\linewidth-2\tabcolsep}p{\dimexpr.19540000000000003\linewidth-2\tabcolsep}p{\dimexpr.1541\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}No.  & Author  & No. of worms used & Culture conditions  & Gene tested  & \multicolumn{2}{p{\dimexpr(.3495\linewidth-2\tabcolsep)}}{\cAlignHack Lifespan (days)}\\
\rowcolor{kwdboxcolor} &  &  &  &  & Mean & Median\\
\tblmidrule 
1 &
  \unskip~\citep{735632:17464645} &
  50-65  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  Numr-1(ok2239)b \mbox{}\protect\newline Numr-1(tm2775)b \mbox{}\protect\newline Transgenic strains: \mbox{}\protect\newline JF88(mtEx63)c \mbox{}\protect\newline TJ356(zIs356)[daf-16;rol-6]c  &
  \ensuremath{\downarrow} (No numerical data)  \mbox{}\protect\newline \ensuremath{\downarrow} (No numerical data)  \mbox{}\protect\newline \ensuremath{\uparrow} (No numerical data)  \mbox{}\protect\newline \ensuremath{\uparrow} (No numerical data)  &
  (No numerical data)  \mbox{}\protect\newline (No numerical data)  \mbox{}\protect\newline 9 \mbox{}\protect\newline 9\\
2 &
  \unskip~\citep{735632:17464516} &
  100  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Skn-1(zu135)b \mbox{}\protect\newline Ife-2(eIF4F)b \mbox{}\protect\newline Skn-1;ife-2b \mbox{}\protect\newline Ifg-1(eIF4F)b \mbox{}\protect\newline Skn-1;ifg-1b \mbox{}\protect\newline Eif-1(PIC)b \mbox{}\protect\newline Skn-1;eif-1b \mbox{}\protect\newline eIF-1A(PIC)b \mbox{}\protect\newline Skn-1;eIF-1Ab \mbox{}\protect\newline Skn-1(zu67)b \mbox{}\protect\newline Skn-1;ife-2b \mbox{}\protect\newline Skn-1;ifg-1b \mbox{}\protect\newline Skn-1;eif-1b \mbox{}\protect\newline Daf-16(mgDf47)b \mbox{}\protect\newline Daf-16;ife-2b \mbox{}\protect\newline Daf-16;skn-1b \mbox{}\protect\newline Daf-16;ifg-1b \mbox{}\protect\newline Daf-16;skn-1 ifg-1b \mbox{}\protect\newline Daf-16;eif-1b \mbox{}\protect\newline Daf-16;skn-1;eif-1b  &
  22.64\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\downarrow}20.29\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\uparrow}24.86\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}21.11\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}27.91\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\uparrow}26.21\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\uparrow}28.16\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\downarrow}22.18\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\uparrow}26.84\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\downarrow}21.62\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}18.33\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}18.31\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}25.88\ensuremath{\pm}0.6 \mbox{}\protect\newline \ensuremath{\downarrow}20.42\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}19.74\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}19.77\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}16.91\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\uparrow}23.61\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}18.72\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\downarrow}20.91\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}16.42\ensuremath{\pm}0.2  &
  23.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\uparrow}25.0 \mbox{}\protect\newline \ensuremath{\downarrow}19.0 \mbox{}\protect\newline \ensuremath{\uparrow}28.0 \mbox{}\protect\newline \ensuremath{\uparrow}25.0 \mbox{}\protect\newline \ensuremath{\uparrow}29.0 \mbox{}\protect\newline 23.0 \mbox{}\protect\newline \ensuremath{\uparrow}27.0 \mbox{}\protect\newline \ensuremath{\downarrow}22.0 \mbox{}\protect\newline \ensuremath{\downarrow}17.0 \mbox{}\protect\newline \ensuremath{\downarrow}17.0 \mbox{}\protect\newline \ensuremath{\uparrow}26.0 \mbox{}\protect\newline \ensuremath{\downarrow}19.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\downarrow}20.0 \mbox{}\protect\newline \ensuremath{\downarrow}17.0 \mbox{}\protect\newline \ensuremath{\uparrow}25.0 \mbox{}\protect\newline \ensuremath{\downarrow}18.0 \mbox{}\protect\newline \ensuremath{\downarrow}21.0 \mbox{}\protect\newline \ensuremath{\downarrow}16.0 \\
3 &
  \unskip~\citep{735632:17464618} &
  30  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Smg-1(tm869)b \mbox{}\protect\newline Rrf-3(pk1426)b \mbox{}\protect\newline Daf-18(e1375);rrf-3b \mbox{}\protect\newline Tax-4(p678);rrf-3b  &
  16.2\ensuremath{\pm}0.4 \mbox{}\protect\newline \ensuremath{\uparrow}19.8\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\uparrow}16.9\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\downarrow}12.7\ensuremath{\pm}0.2 \mbox{}\protect\newline \ensuremath{\uparrow}22.6\ensuremath{\pm}0.5  &
  15.0 \mbox{}\protect\newline \ensuremath{\uparrow}21.0 \mbox{}\protect\newline 15.0 \mbox{}\protect\newline \ensuremath{\downarrow}12.0 \mbox{}\protect\newline \ensuremath{\uparrow}24.0 \\
\multicolumn{1}{p{\dimexpr(.0658\linewidth-2\tabcolsep)}}{\multirow{7}{\linewidth}{4}} &
  \multicolumn{1}{p{\dimexpr(.11830000000000002\linewidth-2\tabcolsep)}}{\multirow{7}{\linewidth}{\unskip~\citep{735632:17464634}}} &
  499  &
  \multicolumn{1}{p{\dimexpr(.10940000000000001\linewidth-2\tabcolsep)}}{\multirow{7}{\linewidth}{20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50}} &
  N2a  &
  16.91 &
  16.13 \\
 &
   &
  306  &
   &
  Age-1(hx546)b  &
  \ensuremath{\downarrow}15.90 &
  \ensuremath{\downarrow}13.21\\
 &
   &
  360  &
   &
  Akt-2(ok393)b  &
  \ensuremath{\uparrow}19.62 &
  \ensuremath{\uparrow}18.66\\
 &
   &
  321  &
   &
  Daf-2(m577)b  &
  \ensuremath{\uparrow}18.53 &
  \ensuremath{\downarrow}16.03\\
 &
   &
  171  &
   &
  Daf-12(m20)b  &
  \ensuremath{\downarrow}10.53 &
  \ensuremath{\downarrow}9.42\\
 &
   &
  709  &
   &
  Daf-16(mgDf50)b  &
  \ensuremath{\downarrow}11.79 &
  \ensuremath{\downarrow}11.35\\
 &
   &
  149  &
   &
  Skn-1(zu67)b  &
  \ensuremath{\downarrow}9.19 &
  \ensuremath{\downarrow}8.46\\
\multicolumn{1}{p{\dimexpr(.0658\linewidth-2\tabcolsep)}}{\multirow{5}{\linewidth}{5}} &
  \multicolumn{1}{p{\dimexpr(.11830000000000002\linewidth-2\tabcolsep)}}{\multirow{5}{\linewidth}{\unskip~\citep{735632:17464653}}} &
  246  &
  \multicolumn{1}{p{\dimexpr(.10940000000000001\linewidth-2\tabcolsep)}}{\multirow{5}{\linewidth}{20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50}} &
  N2a  &
  14.3 &
  13\\
 &
   &
  279  &
   &
  Daf-2(e1370)b  &
  \ensuremath{\uparrow}48.9 &
  \ensuremath{\uparrow}49.0\\
 &
   &
  232  &
   &
  Egl-27(we3)b  &
  \ensuremath{\uparrow}27.8 &
  \ensuremath{\uparrow}28.0\\
 &
   &
  209  &
   &
  Daf-2;daf-16(mu86)b  &
  \ensuremath{\uparrow}24.0 &
  \ensuremath{\uparrow}25.0\\
 &
   &
  234  &
   &
  Daf-2;egl-27(we3)b  &
  \ensuremath{\uparrow}21.5 &
  \ensuremath{\uparrow}20.0\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{\textit{*NGM = Nematode Growth Medium}}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{ThreePartTable}

\centering 
\begingroup
\makeatletter\if@twocolumn\@ifundefined{theposttbl}{\gdef\TwoColDocument{true}\onecolumn\onecolumn}{}\fi\makeatother 
\begin{TableNotes}\footnotesize 
    
\item{*NGM = Nematode Growth Medium}
\end{TableNotes}\setlength\LTcapwidth{\textwidth}
\begin{longtable}{p{\dimexpr.0815\linewidth-2\tabcolsep}p{\dimexpr.13010000000000002\linewidth-2\tabcolsep}p{\dimexpr.1381\linewidth-2\tabcolsep}p{\dimexpr.1496\linewidth-2\tabcolsep}p{\dimexpr.27529999999999998\linewidth-2\tabcolsep}p{\dimexpr.22540000000000003\linewidth-2\tabcolsep}}
\caption{\boldmath {Effect of differential genes expression on the median lifespan of \textit{C. elegans}} }
\label{tw-6195af99a064}
\def\arraystretch{1.1}\\\endfirsthead \hline \noalign{\vskip3pt} \noalign{\textit{Table \thetable\ continued}} \noalign{\vskip3pt} 
\tbltoprule \rowcolor{kwdboxcolor}No.  & Author  & No. of worms used & Culture conditions  & Gene tested  & Median\\
\tblmidrule \endhead \hline \noalign{\vskip3pt} \noalign{\textit{\hfill Continued on next page}} \noalign{\vskip3pt} \endfoot \insertTableNotes \endlastfoot 
\tbltoprule \rowcolor{kwdboxcolor}No.  & Author  & No. of worms used & Culture conditions  & Gene tested  & Median\\
\tblmidrule 
1 &
  \unskip~\citep{735632:17464501} &
  300  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a  \mbox{}\protect\newline Sir-2.1(ok434)b \mbox{}\protect\newline Daf-16(mgDf50)b \mbox{}\protect\newline Daf-2(e1370)b  &
  15.0 \mbox{}\protect\newline No effect \mbox{}\protect\newline No effect \mbox{}\protect\newline \ensuremath{\uparrow}20.0 \\
2 &
  \unskip~\citep{735632:17464510} &
  85-125  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Oga-1(ok1207)b \mbox{}\protect\newline Ogt-1(ok1474)b \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Age-1(hx546)b \mbox{}\protect\newline Sgk-1(ok538)b \mbox{}\protect\newline Pdk-1(mg142)b \mbox{}\protect\newline Akt-1(mg144)b  &
  15.9\ensuremath{\pm}3.6 \mbox{}\protect\newline \ensuremath{\uparrow}20.9\ensuremath{\pm}4.1 \mbox{}\protect\newline \ensuremath{\downarrow}12.9\ensuremath{\pm}1.9 \mbox{}\protect\newline \ensuremath{\uparrow}28.6\ensuremath{\pm}3.5 \mbox{}\protect\newline \ensuremath{\downarrow}14.3\ensuremath{\pm}2.5 \mbox{}\protect\newline \ensuremath{\uparrow}25.6\ensuremath{\pm}4.1 \mbox{}\protect\newline \ensuremath{\uparrow}29.8\ensuremath{\pm}3.2 \mbox{}\protect\newline \ensuremath{\downarrow}14.8\ensuremath{\pm}1.7 \mbox{}\protect\newline \ensuremath{\downarrow}11.5\ensuremath{\pm}2.1 \\
3 &
  \unskip~\citep{735632:17464568} &
  300  &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50  &
  N2a \mbox{}\protect\newline Akt-1(ok525)b \mbox{}\protect\newline Akt-2(ok393)b \mbox{}\protect\newline Sgk-1(ok538)b  &
  36.0 \mbox{}\protect\newline No effect  \mbox{}\protect\newline \ensuremath{\uparrow}40.0 \mbox{}\protect\newline \ensuremath{\downarrow}35.0 \\
4 &
  \unskip~\citep{735632:17464641} &
  30 &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Daf-16(mu86)b \mbox{}\protect\newline Aars-2b  &
  20.0 \mbox{}\protect\newline \ensuremath{\downarrow}15.0 \mbox{}\protect\newline \ensuremath{\uparrow}22.0\\
5 &
  \unskip~\citep{735632:17464630} &
  No data &
  20\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a  \mbox{}\protect\newline His-72(tm2066);his-71(ok2289)b \mbox{}\protect\newline His-72p::his-72::GFPb \mbox{}\protect\newline Daf-2(e1370)b \mbox{}\protect\newline Daf-2;his-72b \mbox{}\protect\newline Daf-2; his-72;his-71b \mbox{}\protect\newline Daf-16(mu86);daf-2b \mbox{}\protect\newline Daf-16;daf-2;his- 72;his-71b \mbox{}\protect\newline His-72p::hh3.3::ha; his- 71p::hh3.3::mycb \mbox{}\protect\newline Nuo-6(qm200)b \mbox{}\protect\newline Nuo-6(qm200); his-72;his- 71b  &
  24\ensuremath{\pm}1.1 \mbox{}\protect\newline No effect (24\ensuremath{\pm}1.5) \mbox{}\protect\newline \ensuremath{\uparrow}25\ensuremath{\pm}1.4 \mbox{}\protect\newline \ensuremath{\uparrow}44\ensuremath{\pm}4.4 \mbox{}\protect\newline \ensuremath{\uparrow}40\ensuremath{\pm}1.4 \mbox{}\protect\newline \ensuremath{\uparrow}32\ensuremath{\pm}5.9 \mbox{}\protect\newline \ensuremath{\downarrow}15\ensuremath{\pm}0.3 \mbox{}\protect\newline \ensuremath{\downarrow}15\ensuremath{\pm}0.7 \mbox{}\protect\newline No effect (24\ensuremath{\pm}0.7) \mbox{}\protect\newline \ensuremath{\uparrow}30\ensuremath{\pm}4.0 \mbox{}\protect\newline \ensuremath{\downarrow}19\ensuremath{\pm}1.5\\
 &
   &
   &
  25\ensuremath{^\circ}C \mbox{}\protect\newline *NGM \mbox{}\protect\newline E. coli OP50 &
  N2a \mbox{}\protect\newline Glp-1(bn18)b \mbox{}\protect\newline Glp-1;his-72(tm2066);his- 71(ok2289)b \mbox{}\protect\newline Glp-1;his-72p::hH3.3::HA; his-71p::hH3.3::Mycb \mbox{}\protect\newline Glp-1;his-72;his- 71;his-72p::his-72::GFPb \mbox{}\protect\newline Glp-1;his-72b \mbox{}\protect\newline Glp-1;his-71b &
  16\ensuremath{\pm}0.7 \mbox{}\protect\newline \ensuremath{\uparrow}26\ensuremath{\pm}0.5 \mbox{}\protect\newline \ensuremath{\uparrow}19\ensuremath{\pm}1.3 \mbox{}\protect\newline \ensuremath{\uparrow}23\ensuremath{\pm}1.2 \mbox{}\protect\newline \ensuremath{\uparrow}22\ensuremath{\pm}1.2 \mbox{}\protect\newline \ensuremath{\uparrow}25.0 \mbox{}\protect\newline \ensuremath{\uparrow}25\ensuremath{\pm}0.3\\
\tblbottomrule 
\end{longtable}
\endgroup
\end{ThreePartTable}

\makeatletter\@ifundefined{TwoColDocument}{}{\twocolumn}\makeatother 

\bgroup
\fixFloatSize{images/a30e2343-2581-4b78-8d1b-90a9531caa25-ucapture2.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/a30e2343-2581-4b78-8d1b-90a9531caa25-ucapture2.png}{\includegraphics{images/a30e2343-2581-4b78-8d1b-90a9531caa25-ucapture2.png}}{}
\makeatother 
\caption{\boldmath {Flow chart of the search stratergy and study selection process}}
\label{f-3b1844cbfd59}
\end{figure*}
\egroup
\textit{age-1, skn-1, hsf-1}, and \textit{sir-2.1} genes, which are all involved in the IIS pathway. Most of the studies found that knockdown of \textit{daf-2} and \textit{age-1} genes extended lifespan while knockdown of genes such as \textit{daf-16}, \textit{skn-1}, \textit{hsf-1}, and \textit{sir-2.1} resulted in a shortened lifespan. 

\textit{C. elegans} is known to live between 25-30 days in normal conditions. A total of 51 studies have demonstrated that the lifespan of \textit{C. elegans} was extended by 2-fold following depletion of \textit{daf-2} expression. The increased lifespan could be due to the fact that inhibition of DAF-2 causes decreased of its binding to the insulin receptor substrate (IRS)/IST-1 leading to dephosphorylate and deactivate phosphoinositidase-3 kinase (AGE-1) that encodes phosphatidylinositol-3-OH kinase (P13K) which responsible to convert phosphatidylinositol-3 (PIP\ensuremath{_{3}}) to phosphatidylinositol-2 (PIP\ensuremath{_{2}}) \unskip~\citep{735632:17464496}. Decreased PIP\ensuremath{_{3}} level will dephosphorylate phosphoinositide-dependent kinase 1 (PDK-1), serine/threonine-specific protein kinase B (AKT-1/2) \unskip~\citep{735632:17464508} and glucocorticoid-inducible kinase-1 (SGK-1) which will then activate DAF-16 (downstream transcription factor FOXO). Hence, enhanced cytoplasm-to-nucleus translocation will activate expressions of genes that lead to longevity \unskip~\citep{735632:17464474} such as heat shock proteins (HSPs) and antioxidants \unskip~\citep{735632:17464493}. Studies in this review showed an extended lifespan of \textit{daf-2} knockdown to be around 30 to 45 days. Most of the studies used \textit{daf-2(e1370)} strain as \textit{daf-2} knockdown mutant because other \textit{daf-2} mutant strains such as \textit{daf-2(m41)} is a class 1 allele of \textit{daf-2} mutant while \textit{daf-2(e1370)} is a class 2 allele. \textit{Daf-2(m41)} mutations trigger dauer formation at 25\ensuremath{^\circ}C. Other than that, it is temperature-sensitive and less pleiotropic than alleles such as \textit{daf-2(e1370)}\unskip~\citep{735632:17464487}. Therefore, \textit{daf-2(e1370)} is considered to be the most ideal strain for studying \textit{daf-2} in influencing \textit{C. elegan's} lifespan. Lifespan extension of knockdown \textit{daf-2} mutants depends on transcription factors DAF-16 and DAF-12 \unskip~\citep{735632:17464506,735632:17464491,735632:17464502}. Different \textit{daf-2} class mutants and corresponding phenotypic traits are believed to result in a common and different downstream unknown complex processes that influence regulation of \textit{daf-16} gene product \unskip~\citep{735632:17464487,735632:17464505}. 

Furthermore, the results from 40 studies showed a decrement of \textit{C. elegans}'s lifespan following \textit{daf-16} knockdown. The \textit{C. elegans} IIS pathway connects nutrient levels to metabolism, growth, development, longevity, and behaviour \unskip~\citep{735632:17464489}. This pathway is regulated by the binding of insulin-like peptide ligands (ILPs) to the insulin/IGF-1 trans-membrane receptor (IGFR) ortholog DAF-2, which then influences the activation of DAF-16 and transcriptional activity of a gene that prolong lifespan. Therefore, knockdown of \textit{daf-16} results in a shortened lifespan. Studies reported in this review found a reduction in the lifespan of \textit{daf-16} knockdown mutant when compared to wild-type. Based on the studies reviewed, \textit{daf-16} mutant \textit{C. elegans} live approximately 8 to 20 days. A total of 21 studies used \textit{daf-16(mgDf50)} strain as \textit{daf-16} mutant. \textit{Daf-16(mgDf50)} strain is a mutant with complete elimination of the \textit{daf-16} coding region. This is considered to be the most ideal strain to be used to study the effect of \textit{daf-16} on the lifespan of \textit{C. elegans}. Another optimal \textit{daf-16} mutant strain used is \textit{daf-16(mu86)} mutant, which is a dauer defective worm. Dauer is a stage where the nematodes are on its defensive mode when unfavourable conditions are encountered. At the dauer stage, the nematode produces a cuticle that coats their body for protection and halts eating hence to suspend growth \unskip~\citep{735632:17464476}. This strain is commonly used to study the effect of environmental stressors on the worms' lifespan because the dauer stage helps the nematodes to survive in unfavourable conditions \unskip~\citep{735632:17464483}.

The knockdown of \textit{age-1} expression increases \textit{C. elegans} lifespan, as reported by 13 studies. The inhibition of AGE-1 contributes to the extension of lifespan as it plays a vital role in the production of PIP\ensuremath{_{3.\ }} The decreased activity of AGE-1 will increase the activity of PTEN phosphatase (DAF-18) and decrease the activity of phosphoinositide-3 kinase, which converts PIP\ensuremath{_{3}} to PIP\ensuremath{_{2}}\unskip~\cite{735632:17464496}. Decreased PIP\ensuremath{_{3}} levels lead to decreased activities of PDK-1 and AKT-1/2 as well as activation of DAF-16, which promotes longevity \unskip~\citep{735632:17464508}. Studies included in this review reported lifespan extension of \textit{age-1} knockdown mutants to be around 17 to 47 days. The \textit{age-1(hx546)} strain was used in these studies mainly because \textit{age-1} mutants have a long life with normal fertility and good tolerance to stress and temperature changes \unskip~\citep{735632:17464486}. 

SKN-1 function as cofactors of DAF-16. Similar to in \textit{daf-16}, \textit{skn-1} is also needed for the extension of lifespan \unskip~\citep{735632:17464484}. This is because SKN-1 plays a major role in various crucial processes needed for lifespan extension, such as protein synthesis in the endoplasmic reticulum (ER), metabolism, and maintaining protein homeostasis when under normal conditions and also when in response to stresses \unskip~\citep{735632:17464477} SKN-1 also contributes to protection against pathogenic infection, which improves the survival of \textit{C. elegans}\unskip~\citep{735632:17464507}. The study was done by \unskip~\citep{735632:17464511}, showed an increased in \textit{C. elegans}'s lifespan following the \textit{skn-1 } knockdown. However, seven other studies reported the opposite where knockdown of \textit{skn-1} is found to decrease the lifespan of \textit{C. elegans}. SKN-1 is critical for oxidative stress resistance and promotes longevity under reduced IIS signaling, dietary restriction (DR), and normal conditions \unskip~\citep{735632:17464514}. 

One of the most important downstream transcription factors of IIS is heat shock transcription factor 1 (HSF-1). HSF plays essential and evolutionary conserved roles in the activation of heat shock-inducible gene expression. HSFs are recognized as regulators of stress-induced gene expression, besides contributing to more complex organismal physiological processes such as development, growth, aging, immunity, and reproduction. HSF-1 is also known to regulate protein folding and gene expression in response to heat stress.  It modulates longevity by upregulating the chaperone network and enhancing the proper folding of proteins \unskip~\citep{735632:17464492,735632:17464503,735632:17464482}. Some studies reported that knockdown of \textit{hsf-1} gene decreases the lifespan of \textit{C. elegans} by about 8\% from wild-type. Heat shock protein-90 (HSP-90) is another chaperone protein which helps to repair misfolded proteins that accumulate during stress. This protein also has essential functions in protein synthesis, processing, and degradation, which are activated by an exertion of HSF-1 cytoplasm-to- nucleus translocation \unskip~\citep{735632:17464509,735632:17464518}. HSF-1 acts in parallel with DAF-16 to provide pathogen resistance hence extending lifespan. A study done on HSF-1 showed that overexpression of \textit{hsf-1} significantly enhanced \textit{C. elegans} resistance to \textit{P. aeruginosa} infection. This indicated that the chaperone system recognized and degraded bacterial virulence factors or functions by proper folding of effector molecules in the immune system \unskip~\citep{735632:17464512}. Studies have shown that knockdown of \textit{hsf-1} drastically reduces the lifespan of \textit{C. elegans}. Transcription factor HSF-1 guides DAF-16/FOXO activity and cooperatively induce transcription of a subset of target genes, including HSPs involved in proteostasis. \textit{Daf-16}, \textit{hsf-1, }and \textit{skn-1} mutants have been to be more sensitive to oxidative and thermal stress as compared to the wild-type nematodes \unskip~\citep{735632:17464492,735632:17464515}.

SIR-2.1 is a sirtuin, member of the nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase. It is directly linked to cellular nutrient signaling through NAD\ensuremath{^{+ }}\unskip~\citep{735632:17464488,735632:17464490}. SIR-2.1 is responsive to metabolic changes in the cellular environment, including nutrient/energy availability and cellular stress \unskip~\citep{735632:17464499}. SIR-2.1 increases the lifespan of \textit{C. elegans} through DAF-16 \unskip~\citep{735632:17464513}. SIR-2.1 binds to DAF-16 in response to cellular stress and promotes DAF-16 activation that results in longevity. A total of ten studies determined the effect of \textit{sir-2.1} gene on the lifespan of \textit{C. elegans}. Most of these studies showed consistent effects of SIR-2.1 on the lifespan. A total of five studies found a reduction in lifespan when \textit{sir-2.1} was knockdown, while four studies showed an increased in lifespan when \textit{sir-2.1} was overexpressed. In contrast, a study done by \unskip~\citep{735632:17464501}  found that \textit{sir-2.1} had no effect on the lifespan of \textit{C. elegans}. SIR2 is a positive regulator of lifespan in \textit{Saccharomyces cerevisiae} and in \textit{C. elegans}\unskip~\citep{735632:17464494}. Overexpression of \textit{sir-2.1}, the \textit{C. elegans} homolog of SIR2, has been reported to extend lifespan in a DAF-16-dependent manner. SIR-2.1 binds to DAF-16 in response to cellular stress and promote DAF-16 activation, which leads to longevity. All of the studies in this review used \textit{sir-2.1(ok434)} strain as \textit{sir-2.1} mutant except for study done by \unskip~\citep{735632:17464516}, which used \textit{sir-2.1(zu67)} strain. Studies in this review showed lifespan extension of \textit{sir-2.1} overexpression to be around 13 to 28 days while \textit{sir-2.1} knockdown decreased lifespan to around 12 to 17 days. 

Variations in the number of days of survival seen in the studies reported here were mostly due to the difference in the experimental conditions used. \textit{C. elegans} survived well between 15\ensuremath{^\circ}C - 25\ensuremath{^\circ}C. The worms will enter a stage of dauer at temperatures beyond this range. Experiments carried out at 25\ensuremath{^\circ}C observed a shorter lifespan of the nematode as compared to 20\ensuremath{^\circ}C. Elsewhere studies performed at 15\ensuremath{^\circ}C found the longer average lifespan of \textit{C. elegans}. \textit{Escherichia coli} strain OP50 (\textit{E. coli} OP50) and Nematode Growth Medium (NGM) are standard laboratory \textit{C. elegans} food and media as it has been used in \textit{C. elegans} research for decades. Different strains of \textit{E. coli} did not show any prominent effects on lifespan. However, a higher mean lifespan was observed in worms fed with live OP50 under low-density feeding (LDF) conditions (OD=0.18), whereas lower mean lifespan was seen under high-density feeding (HDF) conditions (OD=1.5). This shows that an increasing amount of food correlates with decreased lifespan in adult \textit{C. elegans} as the worms obtain most of their energy from this microbe. \textit{C. elegans} also have a longer lifespan in liquid media as compared to solid media. This is probably due to the lower restriction available in liquid media than in solid media. Besides, additional components such as streptomycin, ampicillin, and nystatin in NGM may help to prevent contamination of the media.

A few studies have reported on the effect of \textit{ins-18}\textit{, } \textit{numr-1/-2, sgk-1}, and \textit{rgs-1} genes on the lifespan of \textit{C. elegans}, although these genes play vital roles in resistance. Results found by \unskip~\cite{735632:17464619} indicated that at the adult stage, \textit{ins-18} is needed for lifespan enhancement. According to his study, deletion of \textit{ins-18} due to the relative dominance of agonist binding to DAF-2 reduced larval diapause. The over expression of \textit{ins-18} induced larval diapause, which is important for defence against pathogen. High levels of INS-18 will bind to DAF-2 and inhibit agonist binding, thus preventing the binding of other DAF-2 agonists. Based on the results, it was concluded that \textit{ins-18} is required for longevity. The expression of \textit{numr-1/-2} is associated with resistance to metal toxicity. Knockdown of \textit{numr-1/-2} expression increased sensitivity to cadmium exposure while over expression of \textit{numr-1/-2} increases lifespan in the presence and absence of metal. However, under control conditions, lower expression of \textit{numr-1/-2} does not significantly reduce wild-type lifespan, but in the presence of metals, lower lifespan is observed. This suggests that \textit{numr-1/-2} contribution for longer lifespan needs to be accompanied with other genes. According to the result shown in the sequence analysis of \textit{numr-1} and \textit{numr-2}, the regulatory regions of \textit{numr-1/-2} contain consensus binding sites for both SKN-1 and DAF-16. \textit{Numr-1} and \textit{numr-2} may perform the biological activities necessary to increase resistance and longevity that are mediated by the IIS pathway \unskip~\citep{735632:17464481}. Two of the studies from this review were done on \textit{sgk-1}, which act downstream of \textit{daf-2} in the IIS pathway shows an increased in lifespan \unskip~\citep{735632:17464510,735632:17464473}. Serum-and glucocorticoid-regulated kinase gene (\textit{sgk-1) }act similar to \textit{Akt-1} in lifespan control by phosphorylating and inhibiting the nuclear translocation of DAF-16/FOXO \unskip~\citep{735632:17464480}. The regulator of G protein signaling-1 (\textit{rgs-1}) plays an important role in paraquat-induced oxidative stress \unskip~\citep{735632:17464517}. As compared to wild-type, \textit{rgs-1(nr2017)} mutant displayed significant resistance to paraquat (PQ) toxicity, where a 20\% increase in mean survival time was observed. \textit{Rgs-1} mutant results in a decrease in overall ROS levels compared to wild-type after PQ exposure. This suggests that RGS-1 modulates PQ resistance in a DAF-16-dependent manner. Both of the \textit{daf-16(mu86);rgs-1(nr2017)} double mutant and \textit{daf-16(mu86)} single mutant were sensitive to PQ. The effect of RGS-1 was completely suppressed by the \textit{daf-16} mutant, indicating that \textit{rgs-1} depends on \textit{daf-16} to modulate PQ resistance. Loss of \textit{rgs-1} promotes lifespan relying on \textit{age-1} and \textit{daf-16} as rgs-1 showed significant extension in mean lifespan. A shorter lifespan was seen in \textit{daf-16(mu86)} than wild-type but had a similar lifespan to the \textit{daf-16(mu86);rgs-1(nr2017)} suggesting that the long-lived phenotype associated with \textit{rgs-1} requires \textit{daf-16}\unskip~\citep{735632:17464500}. 

Genes in the insulin/insulin-like signaling (IIS) pathway influences the lifespan of \textit{C. elegans} by regulating vital pathways for the survival of the worm. Knockdown of genes, namely, \textit{daf-2 }and\textit{ age-1} and overexpression of \textit{hsf-1, daf-16, skn-1}, and \textit{sir-2.1}, have been unanimously reported to promote longevity. The roles of these genes have well been established previously. However, whether the modulation of expression of these genes also leads to improved healthspan of the worms is still unclear. The results of these studies renders future researchers to study the effect of the homologous genes in higher-order organismal such as mice, to establish the possibility of lifespan extension through modulation of genes expression and to elucidate the healthspan of organisms with a prolonged lifespan. 
    
\section{Conclusions}
The documented evidence in this review suggests that IIS pathway genes influence the lifespan of \textit{C. elegans} through various mechanisms. Since their roles are well conserved in \textit{C. elegans}. These genes may be targets for future interventional studies aimed to enhance longevity. 

\textbf{Acknowledgement}

This research was funded by the Ministry of Higher Education, grant number FRGS/1/2017/SKK08/UKM. 
    

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