| dve-1 | DVE (Defective proVEntriculus in Drosophila) homolog) 1 | dve-1 RNAi attenuates lifespan extension by bDR, but only partially that of daf-2 mutation. dve-1 RNAi attenuates protection against oxidative stress by bDR. dve-1 expression is not induced by bDR [19924292].
| Nematode |
| eat-2 | EATing: abnormal pharyngeal pumping EAT-2 | eat-2 mutations result in partial starvation by disrupting the function of the pharynx and an approximately 50% extension of lifespan. eat-2 mutants life significant longer by up to 57% [9789046]. eat-2(ad1116) mutants have an extended mean, 75%ile and maximum lifespan by 30, 35, and 24% [22810224]. eat-2 RNAi significantly reduces paralysis in Q35YFP or ABeta42 transgenic animals [18331616]. sDR further increases the long lifespan of eat-2 mutants [19239417]. eat-2 mutants live longer than wild-type at high food concentration but are short lived at lower concentrations (via bacterial dilution) [19229346]. eat-2(ad1113) mutation increases mean lifespan by 56% and is non-additive with SCNA overexpression [16782295]. Combining eat-2 mutation with bacterial deprivation DR does not result in an additive increase in lifespan [17081160;17096674]. Loss of function of eat-2 extends lifespan by 20-30%. Lifespan extension is proposed to be similar to DR. eat-2;daf-2 double mutant live longer than daf-2 single mutants [9789046]. Therefore, eat-2 mutants can synergize with daf-2 mutants, but not with clk-1 mutants, for lifespan extension. Lifespan extension conferred by eat-2 is not suppressed by daf-16 mutation [9789046]. | Nematode |
| egl-9 | EGg Laying defective 9 | egl-9 deletion does not affect lifespan under AL. Lifespan extension under modified sDR regimen is diminished by egl-9 mutation. egl-9 mutation significantly suppresses the lifespan extension by a strong loss-of-function allele of eat-2. Lifespan extension by deletion mutants of rsks-1 is fully suppressed by egl-9 mutation [19461873]. | Nematode |
| OSH6 | OxySterol binding protein Homolog 6 | Elevation of OSH6 levels by an ERG6 promoter extends mean, median and maximum replicative lifespan by 39, 52 and 18% which is non-additive with 0.5% glucose restriction. It also extends the lifespan of NYV1 mutant [Geber et al., unpublished].
The long lifespan of Perg6-OSH6 is not further extended by deletion of TOR1 [22622083].
OSH6 overexpression decreases total cellular sterol content and reduces Lst8 protein levels. The CC domain of Osh6 is dispensable for longevity. Deletion of the CC domain leads Osh6 to the late endosome. [Fusheng Tang, personal communication].
OSH6 deletion does not affect lifespan under normal conditions, but it abrogates the lifespan extension by 0.5% glucose restriction [Xia et al. unpublished].
Perg6-OSH6 osh5 double mutant have a lifespan significantly shorter than that of Perg6-OSH6 [Xia et al. upublished]. | Budding yeast |
| elt-3 | Erythroid-Like Transcription factor 3 | Expression of elt-3 decreases with development and aging. elt-3 RNAi extends maximum lifespan and totally cancels out the daf-2 or DR-induced (eat-2) lifespan extension [18662544]. | Nematode |
| SRX1 | SulfiRedoXin 1 | Extra copy of SRX1 counteracts age-related hyperoxidation of Tsa1 and extends replicative lifespan by 15 - 20% in a TSA1-dependent manner. Replicative lifespan extension in sir2;fob1 double mutant by DR is reduced by SRX1 deletion. Wild-type cells require SRX1 to fully extend lifespan. DR fails to further extend replicative lifespan of cells carrying an extra copy of SRX1. Mutation in CDC35 (adenylate cyclase), a genetic mimetic of DR, is dependent on SRX1 to extend replicative lifespan [21884982]. | Budding yeast |
| F57A8.4 | Protein F57A8.4 | F57A8.4 encodes a rhodopsin-like G-protein coupled receptor that is known to sense light [11493519] and is downregulated in space.
Mutation or RNA interference of F57A8.4 extends lifespan on NGM agar covered with killed or live bacteria as well as in liquid culture medium. F57A8.4 RNAi extends the mean, 75%ile and maximum lifespan by 34, 39, and 61%. F57A8.4(tm4341) mutation extends the mean, 75%ile, and maximum lifespan by 18-38, 21-25, and 42-68%. Lifespan extension by gar-3 mutation is not abolished by RNAi inactivation of either daf-16 nor skn-1. eat-2 RNAi shortens the lifespan of F57A8.4 mutants [22768380].
Mutation and RNAi of F57A8.4 suppresses pheromone-induced dauer formation [22768380].
| Nematode |
| faah-1 | Fatty Acid Amide Hydrolase 1 | faah-1 overexpression reduces eicosapentaenoyl ethanolamide (EPEA), palmitoleyol ethanolamide, linoleyol ethanolamide, as well as arachidonoyl ethanolamide (AEA) levels, delays development, increases thermal stress resistance, and was associated with mean and maximum adult lifespan extension by 19 and 35%, respectively, in presence of abundant food but not under (two different protocols of) DR. Overexpression in pharynx was largely sufficient for this lifespan extension [21562563]. | Nematode |
| FET3 | FErrous Transport 3 | FET3 mutation slightly shortens chronological lifespan under AL. Its chronological lifespan is not extended by 0.5% glucose or amino-acid DR [20421943]. FET3 is one of several iron related genes that are up-regulated in response to increasing strength of glucose DR [18679056]. | Budding yeast |
| Indy | I'm not dead yet | Flies heterozygotic for a disruption in Indy gene have extended mean (87-92%) and maximum (45%) lifespan. Homozygotes for the disruption show only a 10 - 20% increase in mean lifespan [11118146]. Heterozygous insertion of a p-element in the non-coding region of Indy locus leads to a reduction in Indy mRNA expression and causes a significant median lifespan extension in male and female by about 29% and 34%, respectively. At normal or high calorie conditions Indy heterozygote mutants have a significant lifespan extension, but under low calorie conditions, Indy heterozygous mutants have minimal median lifespan extension. Reduction of calorie content from high to normal calorie condition results in 19% decline in Indy mRNA and from normal to low calorie condition results in additional 9% decrease in Indy mRNA. Reduction of calorie content from high to normal calorie conditions in heterozygous Indy mutants leads to 20% reduction in Indy mRNA expression without any additional decrease upon further reduction to low calorie food. Maximum lifespan extension is associated with Indy mRNA levels between 25 - 75% of normal. Long-lived heterozygous Indy mutants on high-calorie food and normal wild-type on low-calorie food have several phenotypes in common: 50 - 60 % reduced mRNA expression levels of Ilp2, Ilp3 and Ilp 5; similar high percentage of anti-FOXO-positive nuclei in fat body cells; higher sensitivity to starvation; do not gain weight; similar decrease in triglycerides and fat storage; normal food intake [19470468].
Mutations in Indy dramatically extend lifespan without a loss in fertility, physical activity, flight velocity or metabolic rate [11118146; 12626742]. Indy encodes a high-affinity dicarboxylate/citrate plasma membrane transporter found most abundantly in adult fat body, oenocytes and midgut cells, the primary sites of intermediary metabolism [12391301]. Indy mutation alters metabolism in a manner similiar to DR and mutants have several phenotypes with long-lived DR files in common, including decreases insulin-like signaling, lipid storage, weight gain, and resistance to starvation, and an increase in spontaneous physical activity [19470468].
Of the Indy206 and Indy302 mutation only one of the two has lower mRNA levels and both do not extend lifespan of female flies in any genetic background. In original genetic background only Indy mutation associated with altered RNA expression extends the lifespan of males. This effect is abolished by back-crossing into standard out-bred genetic backgrounds and is associated with an unidentified locus on the X chromosome. Original Indy line with long-lived males is infected by the cytoplasmic Wolbachia. Longevity of Indy males disappear after tetracycline clearance of this endosymbiont [17571923]. | Fruit fly |
| rpr | reaper | Flies with ablated wings caused by overexpressing reaper (UAS-rpr) with a wing-specific Gal4 enhancer trap (1096-Gal4) exhibit only a 14% extension in lifespan compared to controls which exhibit a 61% extension upon DR [22768842]. | Fruit fly |
| Ilp2 | Insulin-like peptide 2 | Flies with an ablation of median neurosecretary cells (which eliminates Ilp2 expression) exhibit a significant increase in mean and maximum lifespan over that of control flies and an increase to oxidative stress and starvation. The mutants also exhibit increased storage of lipid and carbohydrate, reduced fecundity, and reduced tolerance of heat and cold [15708981]. The median and maximum lifespan of females is increased by 33.5% and 40%, respectively. In males the median and maximum lifespan is increased by 10.5% and 27%, respectively [15708981].
Ilp2 RNA interference results in a 24% to 47% increase in median lifespan [19005568].
Ilp2 is transcriptional down-regulated in long-lived mutants. Ilp2 null mutants are significant longer-lived with a 8-13% longer median lifespan, but have a normal DR response. Ilp2 Ilp3 Ilp5 triple null mutants fail to have a normal response to DR. Their response is right shifted, with mutants shorter-lived compared to wild-type on low but longer-lived on high yeast concentrations [20195512]. | Fruit fly |
| foxo | Forkhead box, sub-group O | foxo overexpression extends lifespan. Activation of foxo in the adult pericerbral fat body is sufficient for lifespan extension [15175753]. Overexpression of foxo in the adult adipose tissue alone prolongs lifespan [15192154; 15175753]. Limited activation of foxo reduces the expression of Drosophila insulin-like peptide dilp-2 synthesized in neurons and, represses endogenous insulin-dependent signaling in peripheral fat body [15175753]. foxo is not required for DR, but its activity modulates the response. foxo null mutants are highly and significantly shorter-lived than wild-type on all food dilutions apart from 0.1 SY and under starvation. foxo null mutants are not more sensitive to starvation than wild-type. foxo overexpression in adult fat body under normal nutritional conditions leads to extension of lifespan of females and causes a right shift of the response curve of lifespan to DR [18241326].
Overexpression of dFOXO in adult fat body increases median, by 21-33%, and maximum lifespan as well as lowers the age-specific mortality at all ages, in two independent experiments. Overexpression of dFOXO increases lifespan by lowering the whole mortality trajectory, with no effect on slope (similar to DR). Initiation of dFOXO expression at different ages increases subsequent lifespan with the magnitude of increase decreasing as the animals were put on RU486 (which activates the foxo transgene via UAS) at older ages. The effects of removal of dFOXO overexpression at different ages closely mirrored those of induction of expression and produce shortest lifespan observed in animals taken of RU486 at the earlier ages [17465980].
| Fruit fly |
| FRE6 | Ferric REductase 6 | FRE6 deletion increases mean replicative lifespan by 14% and cancels out the lifespan extending effect of DR [22912585]. | Budding yeast |
| Ghr | Growth hormone receptor | Ghr knockouts (the so called Laron mice) are dwarfs with significantly extended lifespan by 40-50% [12933651]. Ghr-/- mice are significantly longer lived as Ghr+/+ or Ghr+/- mice (by 40-50%) in both females and males [10875265; 19370397]. 30% DR fails to affect overall survival, average or median long-lifespan of Growth hormone receptor knockout (GHRKO) mice and increased maximal lifespan only in females. Insulin sensitivity in GHRKO mutants is greater than in wild-type and is not further increased by DR [16682650]. Intermittent fasting also fails to extend the long lifespan of GHRKO mice [19747233]. Lifespan of mice with a deletion in the Ghr gene live almost 5 years [21123740]. In C57BL/6J this mutation increases life expectancy by 16 to 26% depending on gender [12933651] and in mice of mixed genetic background the increases amounted to 36-55% [9371826]. Serum levels of GH are elevated in mutant mice [9371826] and mutants are smaller than wild-type. IGF-1 and IGFBP-3 levels are also reduced in Ghr mutant mice [10875265]. The age-associated decline in memory retention is delayed in Ghr mutants [11336996]. Overexpression of a growth hormone antagonist (a mutated growth hormone that competes with the endogenous one) has no effect on lifespan [12933651]. | House mouse |
| gpa2 | Guanine nucleotide-binding protein alpha-2 subunit | gpa2 (alias git8) encodes the alpha subunit of a heterotrimeric G protein, which acts downstream of Git3. Git8 activity accelerates aging and inhibits the lifespan-extending effect of DR. Constitutive active mutation of gpa2 decreases chronological lifespan under AL (2% glucose) and almost completely cancels out the lifespan extending effect of DR (0.2% glucose) [19266076]. | Fission yeast |
| GTR1 | GTp binding protein Resemblance 1 | GTR1 deletion decreases mean and maximum replicative lifespan under AL by 36 and 51%, respectively, and cancels out the lifespan extending effect of DR [22912585]. | Budding yeast |
| GUP1 | Glycerol UPtake 1 | GUP1 deletion extends mean and maximum replicative lifespan by 32 and 30%, respectively, as well as chronological lifespan. DR-induced maximal replicative lifespan extension is not further increased by GUP1 deletion, while gup1 mutant displayed longer chronological lifespan under DR [21584246]. | Budding yeast |
| HHF1 | Histone H Four 1 | HHF1 deletion extends mean and maximum replicative by 45 and 69%, respectively, as well as chronological lifespan. Chronological lifespan extension by HHF1 deletion and DR is non-synergistic. DR appears to extend replicative lifespan more when combined with hhf1 mutation, whereas DR does not change hhf1-induced replicative lifespan extension, suggesting a positive interaction [21584246]. | Budding yeast |
| hif-1 | HIF (hypoxia inducible factor) homolog 1 | hif-1 mutation does not suppress lifespan extension of bDR or eat-2 mutation [19372390]. hif-1 deletion extends lifespan by 24% and inhibition of hif-1 by RNAi also extends adult lifespan. hif-1 mutation extends lifespan under AL, but does not further extend lifespan extension under modified sDR. Activation of hif-1 by egl-9 deletion diminishes lifespan extension by modified sDR. hif-1 acts independent of insulin-like signaling: Lifespan extension by hif-1 suppression does not require DAF-16, because inhibition of hif-1 by RNAi extends lifespan of wild-type and daf-16 null mutant to a similar level. hif-1 RNAi further extends the lifespan of daf-2 mutants. hif-1 is in the TOR pathway, downstream of S6K/rsks-1: Inhibition of hif-1 by RNAi does not further extend lifespan of daf-15 heterozygous mutants. Lifespan extension by deletion mutant of rsks-1 is fully suppressed by egl-9 mutation. hif-1 mutation does not further extend rsks-1 lifespan. pha-4 RNAi slightly reduces lifespan in wild-type and hif-1 mutants, but hif-1 mutation extends lifespan of animals treated with control or pha-4 RNAi to a similar level [19461873]. | Nematode |
| hsp-12.6 | Heat Shock Protein | hsp-12.6 loss-of-function mutation significantly extends lifespan under AL and significantly suppresses intermittent fasting (IF)-induced increase in lifespan, to a similar extend to that of daf-16 mutation. HSP-12.6 expression is induced by fasting in various tissues, including body wall muscle and neuronal systems. hsp-16.2 is one of downstream targets of DAF-16 in IF-induced longevity. The extent of IF-induced longevity in daf-16 hsp-12.6 double mutant is similar to that of single hsp-12.6 or daf-16 mutants. hsp-12.6 and daf-16 function in same signaling pathway. Low insulin/IGF-like signaling in daf-2 results in constitutive activation of DAF-16 and higher expression of hsp-12.6 [19079239]. Expression of hsp-16.2 predicts longevity [13-18 in 22829775]. | Nematode |
| HSP12 | Heat Shock Protein 12 | HSP12 deletion slightly increases mean, medium, and maximum replicative lifespan by 24, 27, and 3% under AL, but totally abolishes the lifespan extending effect of moderate DR [Alan Morgan, personal communication; Herbert et al. in press].
HSP12 encodes a small heat-shock protein which mRNA levels increases in response to diverse environmental stresses (including heat-, osmotic-, and oxidative stress) [11102521; 10722658] and its protein levels are induced upon both DR and high osmolarity. However, HSP12 deletion has no effect on resistance to variety of stresses (including oxidative stress). Hsp12 is monomeric, has negligible in vitro protein chaperone activity, and is intrinsically unstructured/unfolded in water, but switches to a dynamic 4-helical conformation upon membrane binding. These all indicates that Hsp12 has membrane-stabilising "lipid chaperone" functions and while its low levels exerts some negative effects on lifespan high levels of Hsp12 are required for DR-induced lifespan extension [Alan Morgan, personal communication; Herbert et al. in press]. | Budding yeast |
| HST2 | Homolog of SIR Two (SIR2) 2 | HST2 overexpression extends replicative lifespan. 0.5% glucose restriction does not increase lifespan of sir2;fob1;hst2 triple mutants [16051752]. DR increases lifespan of all four sir2;fob1;hstX(X = sirtuin) triple mutants [16741098; 17129213]. | Budding yeast |
| HXT17 | HeXose Transporter 17 | HXT17 mutation extends both replicative and chronological lifespan as well as cancels out DR-induced replicative and chronological lifespan extension. Mean and maximum replicative lifespan are extended by 27 and 49%, respectively [21584246]. | Budding yeast |
| Ilp3 | Insulin-like peptide 3 | Ilp3 null mutants have a normal lifespan under AL and a normal DR response. Ilp2 Ilp3 Ilp5 triple null mutants fail to have a normal response to DR. Their response is right shifted, with mutants being shorter-lived compared to wild-type on low but longer-lived on high yeast concentrations [20195512]. | Fruit fly |
