| symbol | name | observation | species | | ERG6 | ERGosterol biosynthesis 6 | Deletion of ERG6 cancels out replicative lifespan extension of 0.5% glucose DR and results under DR also into a shorter replicative lifespan than under AL [18690010].
| Budding yeast | | ERG5 | ERGosterol biosynthesis 5 | Deletion of ERG5 decreases replicative lifespan by 35% in the a strain [18340043], but increases mean chronological lifespan by 26 - 116% (26, 40, 43, 62, 116) in diploid cells [21447998]. Deletion of ERG5 cancels out the replicative lifespan extension of 0.5% glucose restriction [18690010]. | Budding yeast | | ATG17 | AuTophaGy related 17 | ATG17 deletion decreases replicative lifespan under AL and blocks DR-lifespan extension. ATG17 mutant's replicative lifespan decreases by 70% on DR [18690010]. | Budding yeast | | wwp-1 | WW domain Protein (E3 ubiquitin ligase) 1 | RNA interference of wwp-1 decreases median lifespan by 9% in wild-type animals and 24% in daf-2 mutants [18006689]. Loss of wwp-1 function by RNAi or mutation reduces lifespan at 25 degree Celsius, but not 20 degree Celsius. wwp-1 overexpression extends lifespan by up to 20%. Reduced levels of wwp-1 completely suppress the extended longevity of eat-2 mutants. Lifespan of wwp-1 mutants across entire food concentration range by bacterial dilution in liquid culture or on solid plates does not noticeable change. There is no difference in wwp-1 mRNA levels under AL and DR. RNAi reduction of pha-4, but not of daf-16 suppresses increased longevity by wwp-1 overexpression. Mutations in iron sulphur component of complex III, isp-1, increases longevity by reducing mitochondrial function. wwp-1 RNAi does not suppress the extended lifespan of isp-1 mutants and has only minor suppressive effects on lifespan of another mitochondrial mutant, clk-1, and in cyc-1 RNAi treated worms. RNAi depletion of wwp-1 has no effect on long lifespan of daf-2 mutants [19553937]. | Nematode | | skn-1 | SKiNhead 1 | RNA interference of or mutations in skn-1 prevent the life-extension effects of dietary restriction [17538612]. skn-1 transgenes that overexpress a constitutive nuclear form of SKN-1 in the intestine extend the mean lifespan by 5-21%, independently of DAF-16 [18358814]. skn-1 mutation does not alter lifespan under AL, but cancels out the lifespan extension effect of lDR or food variation at all. Response to lDR in skn-1 mutant is restored by ectopic expression of skn-1 in ASI neurons and gut. Ectopic expression of skn-1b in ASI neurons rescued lDR longevity defects of skn-1. Ablation of ASI neurons completely suppresses the response to DR in wild-type or daf-16 mutants and cause a small increase in basal longevity of wild-type but not daf-16 mutants. lDR significantly increases SKN-1 expression in ASI neurons. lDR worms exhibit elevated respiration, which is absent in skn-1 mutants. skn-1 is necessary for increased respiration and the increase in respiration is necessary for lDR longevity effect, because two different inhibitors of mitochondrial electron transport chain complex III, myxothiazol and antimycin, suppress lDR longevity without shortening lifespan under AL. In contrast, the long life of a daf-2 mutant is not affected by antimycin. Some isoforms of SKN-1 are expressed from an operon downstream of bec-1. Beclin-1 mediates autophagy induced by nutrient deprivation. Therefore, skn-1 might be regulated by nutritional stress [17538612]. IF significantly extends lifespan of skn-1 mutants [19079239]. sDR extends lifespan of a skn-1 loss-of-function mutant (which displays a premature stop codon in all three isoforms) and wild-type to a similar extent [19239417].
skn-1(zu67) mutation decreases mean, median, and maximum lifespan by 11-23, 13-28 and 12-23%, respectively, and totally cancels out lifespan extension by ragc-1 RNAi [22560223].
| Nematode | | sir-2.1 | Yeast SIR related 1 | sir-2.1 deletion slightly reduces lifespan of wild-type [16860373]. sir-2.1 overexpression extends lifespan by about 50% and this lifespan extension depends on DAF-16 activity as it is suppressed by mutation in daf-16 and it does not synergize with daf-2 [11242085]. sir-2.1 suppresses longevity of unc-13 and eat-2, but not daf-2 or unc-64 mutants. sir-2.1 is therefore partially required for lifespan extension from mutation of eat-2 [16860373], but is completely independent for lifespan extension from DR using a reduced feeding protocol [Kaeberlein et al. in press]. sDR increases lifespan of wild-type and sir-2.1 mutants to the same extent [19239417].
Overrexpression of sir-2.1 synergizes with TGF-beta mutation (daf-4 and daf-1) for dauer formation [11242085]. | Nematode | | RIM15 | Regulator of IME2 15 | RIM15 deletion results in 50% reduction of maximal chronological lifespan [11292860] and consistently decreases chronological lifespan under AL [21076178]. Rim15 is required for chronological lifespan extension caused by deficiency in RAS2, TOR1, or SCH9, as well as by 0.5% glucose restriction, but not by water starvation [18225956]. | Budding yeast | | RAS2 | Ras-like protein 2 | Overexpression of RAS2 causes a 43% increase in mean and 18% increase in maximum lifespan as well as postpones the age-related increase in generation time. RAS2 deletion causes a 23% decrease in mean and a 30% decrease in maximum lifespan [8034612]. Deletion of RAS2 leads to a longer chronological lifespan [21076178]. Deletion of the RAS2 gene, which functions upstream of CYR1, doubles the mean chronological lifespan by a mechanism that requires Msn2/4 and Sod2 [12586694]. DR further extends chronological lifespan of ras2Delta [18225956]. | Budding yeast | | pha-4 | defective PHArynx development 4 | pha-4 is required for multiple forms of DR. RNAi of pha-4 completely cancels out the lifespan extension of eat-2 mutation. Mutants of pha-4 do not respond to bacterial DR. Therefore, loss of pha-4 completely blocks the response to varying food concentration. Moreover, pha-4 expression is increased in response to DR in wild-type. pha-4 overexpression increases longevity of wild-type only slightly, but significant that of daf-16 mutants. The response to DR involves the PHA-4-dependent expression of sod-1, sod-2 and sod-5. Reduction of pha-4 does not suppress the long lifespan of daf-2 mutants or animals with defective electron transport chain [17476212]. IF significantly extends lifespan of pha-4 [19079239]. sDR extends lifespan of mutants with a temperature sensitive allele of pha-4 or pha-4 RNAi knockdown, but not daf-16 RNAi [19239417]. PHA-4 may play a role in the life-extending effects of dietary restriction. RNAi of pha-4 decreases lifespan of wild-type worms, but not of daf-2 mutants or of animals with defective electron transport chains. | Nematode | | p53 | — | Overexpression of wild-type p53 during adult life has no significant effect on lifespan. Expression of dominant-negative versions of p53 in adult neurons extends lifespan by 58% in females and by 32% in males and increases resistance to genotoxic stress and resistance to oxidative stress, but not to starvation or heat stress, while not affecting egg production or physical activity.
Dominant negative p53 expression cancels out lifespan extension effect of DR, low calorie-food (5% SY). Muscle or fat body specific expression of a dominant negative form of p53 as well as globally lack of p53 decreases lifespan [16303568]. Loss of p53 activity slightly shortens the lifespan. Mutants that lack p53 survive well up to 50 days, but mortality rate increases relative to wild-type at later ages. p53 mutant animals are extremely sensitive to irradiation [12935877].
Expression of dominant-negative (DN) form of p53 in adult neurons, but not in muscle or fat body cells, extends median lifespan by 19% and maximum lifespan by 8%. The lifespan of dietary-restricted flies is not further extended by simultaneously expressing DN-DMp53 in the nervous system, indicating that a decrease in Dmp53 activity may be part of the DR lifespan-extending effect. Selective expression of DN-Dmp53 in only the 14 insulin-producing cell (IPCs) in the brain extends lifespan to the same extent as expression in all neurons and this lifespan extension is not additive with DR [17686972].
| Fruit fly | | hsf-1 | Heat Shock Factor 1 | RNA interference of hsf-1 suppresses normal dauer formation and life-extension due to insulin-like signaling [14668486]. hsf-1 overexpression extends mean, median, and maximum lifespan by 37, 35, and 29%[22737090]. hsf-1 RNAi abrogates lifespan extension by daf-2(e1370) mutation, but not eat-2(ad1116) or isp-1(qm150). HSF-1, like DAF-16, is required for daf-2 mutations to extend lifespan [12750521]. A mutant allele of hsf-1 slightly decreases lifespan under AL, but cancels out the lifespan extension effect of bDR. hsf-1 RNAi also prevents lifespan extension by bDR. bDR significantly reduces paralysis of Q35YFP or ABeta42 transgenic animals and hsf-1 RNAi totally cancels this effect. DR confers a general protective effect against proteotoxicity and promotes longevity by a mechanism involving hsf-1 [18331616]. Glucose or glycerol does not shorten the lifespan of hsf-1 mutants. Glucose treatment completely suppresses the long lifespan caused by hsf-1 overexpression [19883616]. sDR extends the lifespan of hsf-1 mutant with a premature stop codon, that eliminates activation domain, and that of wild-type to a similar extent [19239417]. hsf-1 RNAi attenuates lifespan extension by bDR, but only partially that of daf-2 mutation. hsf-1 RNAi attenuates protection against oxidative stress by bDR. hsf-1 expression is induced by bDR [19924292]. RNAi of hsf-1 shortens median and maximum lifespan by approximately 35%. hsf-1 RNAi animals exhibit phenotypes associated with accelerated aging (as assyed by Nomarsky microscopy) [12136014]. | Nematode | | daf-16 | Abnormal DAuer Formation DAF-16, fork head-related transcription factor (daf-16) | Mutations in daf-16 suppresses life-extension caused by mutations in daf-2 [8247153]. daf-16 is required for lifespan extension by mutation of daf-2 or age-1 [8247153]. RNAi against daf-16 decreases lifespan of wild-type, daf-2 or glp-1 mutants [22509016; 16530050]. Loss of function alleles of daf-16 shorten lifespan, but some alleles have lifespan equal to wild-type [8247153]. daf-16 mutation significantly reduces lifespan under AL (-20%), but does not prevent lifespan extension by sDR. In another experiment daf-16 mutation totally suppresses lifespan extension by sDR [16720740]. sDR does not stimulate DAF-16 translocation to the nucleus, but daf-16 mutation cancels out the ability of sDR to extend lifespan and to delay the decline in locomotor activity [17900900]. DR by bacterial dilution extends lifespan of daf-16 mutants [17538612]. daf-16 mutation decreases lifespan under AL, but fails to prevent bDR to further extend lifespan [18331616]. IF-induced lifespan-extension by either 24h/48h/72h per 4 days is significantly diminished in null mutants of daf-16. All these regimens extend lifespan of daf-16 to a lesser extent than that of wild-type. daf-16 partially mediates IF-induced longevity [19079239]. Glucose or glycerol does not shorten lifespan of daf-16 mutants [19883616]. daf-16 mutation cancels out the lifespan extension effect of sDR and PD, regardless of the concentration of bacteria or peptones. bDR significantly extends lifespan of daf-16 mutants, but to a lesser extent than that of wild-type. eat-2 mutation extends the lifespan of daf-16 mutants to the same extent than that of wild-type. Resveratrol extends lifespan of daf-16 mutants [19239417]. daf-16 RNAi completely blocks the lifespan extension by daf-2 mutation, but only partially by bDR. daf-16 RNAi attenuates protection against oxidative stress by bDR. daf-16 expression is induced by bDR [19924292]. Knockdown of daf-16 decreases mean and maximum lifespan by 50% and 54%, respectively [22509016]. DAF-16 reduces expression of rsks-1 and daf-15 [15253933; 22560223]. daf-16(mgDf47) decreases mean (18-37%) and maximum (29%) lifespan [18828672]. Overexpression of wild-type DAF-16 modestly increases lifespan by 20% [11747825], while overexpression of constitutive nuclear forms of DAF-16 increases lifespan only slightly [11381260]. daf-16(mu86) mutation decreases mean (44%) and maximum (18%) lifespan [15905404]. daf-16(mgDf47) decreases mean (18-37%) and maximum (29%) lifespan [18828672]. daf-16 mutants are dauer defective [7219552] and completely suppress all the phenotypes of daf-2 and age-1 mutations, including lifespan extension, dauer arrest, reduced fertility, and viability defects [8247153; 7789761; 9504918; 7789761]. Mutations in daf-16 also suppress lifespan extension of animals that have a germ line ablation [10360574]. Sex-specific lifespan potential requires daf-16 [10747056].
daf-16 mutation suppresses enhanced UV resistance as well as increase longevity of daf-2, daf-23, spe-26, and clk-1 mutants. Mutation in daf-16 does not alter the reduced fertility in spe-26. daf-16 mutants are more fertile than wild-type [8807294]. | Nematode | | bec-1 | BEClin (human autophagy) homolog 1 | bec-1 is required for normal dauer morphogenesis and lifespan extension. Knockdown of bec-1 via RNA interference results in a shortened mean and maximum lifespan by 14 and 5% [12958363]. bec-1 RNAi does not significantly change the lifespan of wild-type, but completely suppresses the longevity phenotype of eat-2 mutation [17912023; 18282106] and prevents lifespan extension by daf-2(e1370) mutation [12958363]. bec-1 RNAi causes the formation of abnormal dauers in a daf-2(e1379) background [12958363]. | Nematode | | aak-2 | AMP-Activated Kinase 2 | AAK-2 could be a sensor that couples energy levels and insulin-like signals to lifespan. aak-2(ok524) knockout mutants have a 12% and 18% shorter mean and maximum lifespan, respectively as well as faster age-dependent accumulation of a lipofuscin-like fluorescent pigment in the intestine [15574588]. sDR increases AMP:ATP ratio. aak-2 mutation suppresses lifespan extension and delay of the decline in locomotor activity resulting from sDR. A constitutive active mutation of aak-2 is sufficient to cause increase stress resistance as well as to significantly extend lifespan. Both increased stress resistance and extended lifespan is reverted in daf-16 knockdown by RNAi. sod-3 mRNA is increased by constitutive active form of aak-2 and decreased by aak-2 mutation. The increase in sod-3 mRNA is dependent on expression of DAF-16. Worm and human AMPK phosphorylate DAF-16 (greatly enhanced by presence of AMP) at least in six residues (T166, S202, S314, S321, T463 and S466) [17900900]. aak-2 mutation cancels out the lifespan extension effect of sDR and PD, regardless of the concentration of bacteria or peptones. bDR significantly extends lifespan of aak-2 mutants, but to lesser extent than that of wild-type. eat-2 mutation extends the lifespan of aak-2 mutants to the same extent than that of wild-type. Resveratrol does not increase lifespan of aak-2 mutants [19239417]. daf-2(m577);aak-2(ok524) double mutant has a lifespan that is indistinguishable from those of aak-2(ok524) single mutant. Transgenic animals with a higher aak-2 gene dose live on average 13% longer with a maximum lifespan extension on up to 25% [15574588]. | Nematode | |
