| HES1 | Homologous to kES1 1 | Deletion of HES1 (alias OSH5) extends replicative lifespan and is non-additive with moderate DR. Elevation of OSH5 levels by an ERG6 promoter reduces mean, median and maximum replicative lifespan by 25, 18 and 29%. HES1 is required for the longevity effect of DR, Perg6-OSH6, Perg6-ERG2 and Perg6-OSH7 (genetic mimetics of DR). Hes1 is upregulated in response to sterol down-regulation including DR. Deletion of OSH5 delays different steps of endocytosis, a sterol-requireing process [Xia et al., unpublished].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 |
| SWH1 | — | SWH1 (alias OSH1) deletion mutants have an extended replicative lifespan (p=0.02) and DR does not increase the long lifespan of SWH1 deletion mutants [Xia et al. unpublished]. | Budding yeast |
| TCO89 | Tor Complex One | TCO89 deletion increases chronological lifespan, increases mitochondrial oxygen consumption, but decreases mitochondrial and cellular ROS in early stationary phase [21641548]. Deletion of TCO89 cancels out replicative lifespan extension by moderate DR [18690010]. | Budding yeast |
| slcf-1 | SoLute Carrier Family 1 | slcf-1 RNAi or mutation extends the lifespan. slcf-1 mutation increases average lifespan by 40%. DR (by dilution of bacteria on solid medium or by bacterial deprivation) failes to extend slcf-1 mutant's long lifespan and lifespan is even reduced by lowering bacteria concentration (i.e. higher strength of DR) [21040400]. | Nematode |
| PKH2 | Pkb-activating Kinase Homolog 2 | PKH2 deletion increases replicative lifespan by 20% in the alpha strain and by 15% in the a strain [18340043]. Deletion of PKH2 increases chronological lifespan by 29% [22319457] to 34% [21447998] as well as by 19 - 54% (19, 24, 29, 54) in diploid cells [21447998]. PKH2 mutation extends both replicative and chronological lifespan as well as cancels out DR-induced replicative and chronological lifespan extension [21584246]. Mean and maximum replicative lifespan on AL is extended by 38 and 69%, respectively. | Budding yeast |
| NDE1 | NADH Dehydrogenase, External 1 | Overexpression of NDE1 and NDE2 increases intracellular NAD/NADH ratio by lowering NADH concentration and increases replicative lifespan by 20-25%. This lifespan extension is non-additive 0.5% glucose restriction [14724176]. Deletion of NDE1 extends chronological lifespan [16436509]. | Budding yeast |
| IPK1 | Inositol Polyphosphate Kinase 1 | Deletion of IPK1 increases mean replicative lifespan by 41 - 40% in the alpha strain [16293764; 19030232]. IPK1 deletion extends mean and maximum replicative lifespan by 24 and 19%, respectively, and was non-synergistic with moderate DR [21584246]. | Budding yeast |
| GIS1 | GIg1-2 Suppressor 1 | Deletion of GIS1 increases replicative lifespan by 25% in the alpha strain [19030232] and causes major although not complete reversion of chronological lifespan extension by 0.5% glucose restriction [18225956]. | 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 |
| CYR1 | CYclic AMP Requirement 1 | The CDC35-1 allele of the adenylate cyclase CYR1 confers a 75% extension of replicative lifespan at 25 degree Celsius [11000115]. Transposon-mutagenized CYR1 increases resistance to oxidants and extends chronological lifespan by up to 90%. Stress-resistance transcription factors Msn2/Msn4 and protein kinase Rim15 are required for this lifespan extension [11292860]. CYR1 mutation is assumed to act as genetic DR mimetic [11000115]. The CDC35-1 allele of the adenylate cyclase CYR1 confers a 75% extension of replicative lifespan at 25 degree Celsius [11000115]. cyr1-1 mutation extends median chronological lifespan by 28-47% and is non-addative with lifespan extension conferred by overxpression of human MAPK1 [17662940]. | Budding yeast |
| BMH1 | Brain Modulosignalin Homologue 1 | Deleting BMH1 extends chronological lifespan by 25% and is associated with activated stress response, decreased ROS levels and increased heat-shock-element-driven transcription activity. BMH1 deletion was non-additive with the genetic DR mimetic cdc25 and tor1. Water starvation (a form of extreme DR) extends chronological lifespan of BMH1 mutant even more as it does in wild-type. BMH1 genetically interacts with DR as well as TOR- and PKA-signaling pathways to regulate lifespan. Phosphorylation of Ser238 on Bmh1 increases during chronological aging, which is delayed by DR or reduced TOR activity [19805817].
| Budding yeast |
| vit-5 | VITellogenin structural genes (yolk protein genes) 5 | RNA interference against vit-5 extends mean lifespan by 10-22%. vit-5 is differentially transcribed in daf-16 and daf-2 RNAi animals [12845331]. RNAi knockdown of vit-5 starting at hatching or only during the adulthood significantly extends lifespan of wild-type, but does not alter, or even shortens the lifespan of eat-2 mutants [22810224]. | Nematode |
| unc-52 | UNCoordinated 52 | RNA interference of unc-52 in adulthood extends mean lifespan by 11% [17411345]. RNAi knockdown of unc-52 starting at hatching or only during the adulthood significantly decreases lifespan of eat-2 without affecting wild-type lifespan. UNC-52 levels are elevated in eat-2 mutants. Increased content of UNC-52 is, at least partially, required for lifespan-extension by DR [22810224]. | Nematode |
| TOR1 | Target Of Rapamycin 1 | TOR1 deletion extends mean and maximum replicative lifespan by 21 and 25% [16293764] as well as chronological lifespan [21076178]. This lifespan extension is independent of SIR2 and additive with deletion of FOB1 [16293764]. Deletion of TOR1 fails to increase the replicative lifespan of a sir2 mutant [20947565]. Deletion of TOR1 substantially extends chronological lifespan, increasing median survival almost 3-fold (wild-type 4.5 days, tor1 null 12 days), i.e. by 167%. By 21 days in culture, the vast majority of wild-type cells had died (>99.9%), whereas many tor1 null cells remained viable. Deletion of TOR1 also extends the chronological lifespan of the relatively short-lived BY4742 strain, one of the two haploid genetic backgrounds of the widely used Yeast Knockout Collection available from Open Biosystems. Deletion of TOR1 fails to extend chronological lifespan in Petite strains that are unable to respire [17403371]. TOR1 deletion increases replicative lifespan by 30% in the alpha strain and 20% in a strain [19030232]. TOR1 deletion mutant have and increased mean and maximum replicative lifespan by 21% and 6%, respectively [21931558]. Deletion of TOR1 extends replicative lifespan as well as chronological lifespan [21076178] and glucose restriction fails to further extend the long replicative lifespan of tor1Delta [16293764; 16418483; 18225956]. Water starvation (extreme DR) further extends chronological lifespan of tor1 mutants [18225956]. | Budding yeast |
| SCH9 | — | Transposon-mediated mutagenesis of SCH9, which encodes for a serine threonine kinase homologous to Akt/PKB, increases resistance to oxidants and thermal stress as well as extends chronological lifespan by 30%. SCH9 deletion increases chronological lifespan by up to threefold. Stress-resistance transcription factors Msn2/Msn4 and protein kinase Rim15 are required for this life-extension. Deletion of the mitochondrial antioxidant enzyme superoxide dismutase gene SOD2 prevents the increased chronological lifespan caused by SCH9 deletion [11292860]. Mutations that decrease the activity of the Ras/Cyr1/PKA pathway also extend longevity and increase stress resistance by activating transcription factors Msn2/Msn4 and Sod2 [12855292]. SCH9 deletion mutants exhibit more than 3-fold extension of chronological lifespan. By day 9 of medium depletion all the wild-type cells were dead while 50% sch9 mutants survived [17710147]. Deletion of SCH9 also increases resistance to heat shock and oxidative stress [11292860], and increases replicative lifespan by 18% (in DBY746) [12586694]. SCH9 deletion increases the replicative lifespan by 40% in the alpha strain [18340043] and increases mean chronological lifespan by 97 - 246% (97, 133, 154, 226, 246) in diploid cells [21447998]. Mutation or deletion of SCH9 increases resistance to oxidants and extends chronological lifespan [11292860; 16286010]. The extended lifespan of SCH9 deletion mutants is not further extended by low glucose DR and is independent of Sir2 [16293764]. Deletion of RIM15 or GIS1 reverses chronological lifespan extension associated with sch9Delta. Water restriction further increases chronological lifespan of sch9Delta [18225956]. Deletion of SCH9 results in a longer chronological lifespan [21076178]. | Budding yeast |
| sams-1 | S-Adenosyl Methionine Synthetase 1 | sams-1 RNAi significantly extends lifespan of wild-type by 14 - 15%, of daf-16 mutant by 30% and daf-2 by 55%, but fails to significantly further extend lifespan of eat-2 mutants. mRNA level of sams-1 is 2-fold reduced in eat-2 mutants. Like DR, sams-1 RNAi reduces brood size and slightly reproductive timing as well as causes a slender phenotype [16103914]. sams-1 RNAi significantly reduces paralysis in Q35YFP transgenic animals [18331616]. | Nematode |
| S6k | RPS6-p70-protein kinase | Ubiquitous overexpression of a dominant-negative form of S6k (alias dS6K) increases mean lifespan by 22% and overexpression of a constitutively active form of S6k decreases mean lifespan by 34% at 29°C. Overexpression of a dominant-negative form of S6k protects mutants from deleterious effects of rich food, as if mimicking the effect of DR [15186745]. | Fruit fly |
| RPL31A | Ribosomal Protein of the Large subunit 31A | Deletion of RPL31A increases mean replicative lifespan by 45% [16293764]. Mean replicative lifespan increases by 35% in the alpha strain and 50% in a strain [19030232; 18423200]. Mean replicative lifespan of the RPL31A deletion mutant increases by 35% in the ORF collection and by 29% in the remade strain [22377630]. RPL31A deletion increases significantly replicative lifespan [17174052]. Deletion of RPL31A extends replicative lifespan and is not further extended by 0.05% glucose restriction [18423200]. | Budding yeast |
| Rpd3 | Histone deacetylase Rpd3 | Males heterozygous for hypomorphic (partial loss-of-function) or null mutation of Rpd3 have a lifespan extension of 33% and 41 - 47%, respectively. Females heterozygous for a hypomorphic allele have a 52% increase in lifespan, but females carrying a null mutation have only modest increase in maximum lifespan (but not median lifespan). Longevity increases to the same extent in wild-type under low-calorie diet and rpd3 mutants fed normal diet. DR fails to further increase lifespan of rpd3 mutants. DR leads to a moderate but significant down-regulation of Rpd3, analogous to decrease obtained in heterozygotes carrying rpd3 mutation. rpd3 mutants fed normal food and wild-type fed low-calorie increase Sir2 expression two-fold [12459580]. | Fruit fly |
| RPD3 | Reduced Potassium Dependency 3 | Deletion of the histone deacetylase gene RPD3 extends lifespan by 41%, independently of an intact Sir silencing complex (in the short lived YSK661 strain) [10512855]. Deletion of RPD3 extends replicative lifespan and there was no additive effect by neither 0.1% glucose nor amino acid restriction [12213553].
RPD3 deletion increases rDNA silencing in a partially SIR2-dependent manner [10082585].
Its effects on chromatin functional state were evidenced by enhanced silencing at the three known heterochromatic regions in the genome, the silent mating type (HM), subtelomeric, and rDNA loci, which occurred even in the absence of SIR3 [10512855]. | 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 |
| pka1 | cAMP-dependent protein kinase 1 | pka1 knockouts exhibits a three-fold increase in chronological lifespan with up to 187% longer maximum lifespan [16822282]. Deleting ser/thr cAMP-activated protein kinase pka1 extends chronological lifespan under normal condition, but there is no additive effect with DR [20075862]. | Fission yeast |
| 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 |
| Orco | Odorant receptor co-receptor | Loss-of-function mutation in Orco (alias Or83b) results in olfactory defects, altered adult metabolism, enhanced stress resistance, and life-extension. Fully fed female homozygous Or83b null mutants exhibit a 56% increase in median lifespan and a 30% increase in maximum lifespan. Males are also significantly longer-lived, though to a smaller degree and maximum lifespan is not extended. Heterozygous mutants of both sexes show an intermediate longevity. Lifespan of homozygous Orco null mutants is further increased by DR, but the relative increase in median and mean longevity is significantly greater when mutants were maintained in well-fed conditions [17272684].
| Fruit fly |
| ins-7 | INSulin related 7 | RNA interference of ins-7 extends the mean lifespan by 55% at 20 degree Celsius in N2 rrf-3(pk1426) [12845331]. ins-7 RNAi significantly extends lifespan under AL. Treating wild-type with 2% glucose produced pattern of gene expression that overlaps significantly with that produced by genetic inhibition of daf-16 activity in daf-2 mutants. This results in changes in expression of several insulin-like genes, including DAF-16 target gene ins-7. Addition of glucose triggers an increased ins-7:GFP expression. Glucose suppresses the extended lifespan by ins-7 RNAi [19883616]. RNAi of ins-7 does not further extend the lifespan in daf-2 mutants [12845331]. ins-7 is repressed in animals with reduced daf-2 activity and elevuated in animals with reduced daf-16 activity. | Nematode |
