| NPT1 | Nicotinate PhosphoribosylTransferase 1 | Increased dosage of NPT1 increases SIR2-dependent silencing, stabilizes the rDNA locus and extends replicative lifespan by up to 60%. 0.5% glucose restriction does not significantly further increase replicative lifespan of NPT1 overexpression [11884393]. NPT1 deletion decreases replicative lifespan by 50% [17482543] as well as chronological lifespan [17110466]. Deletion of NPT1 shortens the lifespan in W303R. Replicative lifespan extension of cdc25-10 mutation (assumed to act as a genetic DR-mimetic) is cancelled out by NPT1 deletion [11000115].
NPT1 mutation results in loss of telomere and rDNA silencing [10841563], an effect that is likely caused by a loss of SIR2 activty due to decreased NAD levels. Mutation of NPT1 is synthetical lethal with mutation of QPT1 [11000115]. | 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| SIR2 | Silent Information Regulator 2 | Deletion of SIR2 shortens replicative lifespan by approximately 30%. Integration of a second copy of SIR2 into the wild-type strain leads to an extension of replicative lifespan by around 35% in W303R strain [10521401]. Deletion of SIR2 causes genomic instability at rDNA array [2647300] and shortens replicative lifespan by 50% [11000115]. 0.5% glucose restriction fails to increase the short lifespan of sir2Delta [11000115] probably duo to hyperaccumulations of extrachromosomal rDNA circles (ERCs) [16311627]. 0.1% glucose restriction extends replicative lifespan of sir2 mutants [12213553]. 0.5, 0.1 and 0.05% glucose restriction are able to increase lifespan of sir2;fob1 double mutant to a greater extent than in wild-type [15328540]. 0.05% glucose restriction further extends replicative lifespan of SIR2 overexpression mutant [15328540]. Sir2 blocks extreme chronological lifespan extension as the lack of Sir2 along with DR and/or mutations in the yeast AKT homolog, Sch9, or Ras pathways causes a dramatic chronological lifespan extension (6-fold) [16286010]. Sir2 inhibits formation of ERCs and acts on histones as well metabolic enzymes among others. Overexpression extends replicative lifespan in several strains, but not in PSY316 [15684413].
Chronological lifespan of sir2 deletion mutant is significantly extended compared with wild-type in water (extreme DR) but not in saturated cultures containing 2% glucose (ad libitum).
SIR2 mutants are defective for telomere [1913809] and HM silencing [6098447; 3297920]. have increased rDNA recombination [2647300] and a loss of rDNA silencing [9009207; 9009206].
| Budding yeast |
| NNT1 | Nicotinamide N-methylTransferase 1 | Deletion of NNT1 decreases mean and maximum lifespan by 9 and 19%. 0.5% glucose DR extends the mean and maximum lifespan of NNT1 deletion mutants by 35 and 40%. Overexpression of NNT1 by 5-fold extends mean and maximum replicative lifespan by 18 and 23%, which is approximately of the same magnitude as the lifespan extension obtained from DR. DR in NNT1 overexpression mutant fails to significantly affect the lifespan and only results in extended mean lifespan by 12% and reduced maximum lifespan by 11%. NNT1 overexpression increases rDNA silincing, whereas deletion decreases rDNA silencing. Overexpression of human nicotinamide N-methyltransferase also increases rDNA silencing [12736687]. | Budding yeast |
| wis1 | — | Constitutive active mutation of wis1 extends chronological lifespan and there is no further beneficial effect of DR [20075862]. | Fission yeast |
| PNC1 | Pyrazinamidase/NiCotinamidase 1 | Cells with 5 copies of PNC1 have a 70% longer replicative lifespan which is cancelled out by SIR2 deletion. PNC1 is upregulated under glucose DR [12736687]. Pnc1 reduces cellular nicotinamide levels, a product and noncompetitive inhibitor of Sir2 deacetylation reaction. Overexpression of PNC1 suppresses the effect of exogenously added nicotinamide on Sir2-dependent silencing at HM loci, telomeres and rDNA loci [12736687; 14729974]. Pnc1 catalyses the breakdown of nicotinamide to nicotinate and ammonia [12736687]. Deletion of PNC1 shortens replicative lifespan approximately by 10% [12736687] and largely prevents replicative lifespan extension of 0.5% glucose restriction. 0.5% glucose restriction slightly extends median replicative lifespan (by 10 - 15%) but not maximum replicative lifespan in pnc1Delta [14724176]. PNC1 overexpression suppresses the inhibitory effect of exogenously added NAM on silencing, lifespan, and Hst1-mediated transcriptional repression [14729974]. Increased expression of PNC1 is both necessary and sufficient for replicative lifespan extension by DR and low-intensity stress. Under non-stressing conditions (2% glucose, 30 degree Celsius), a strain with additional copies of PNC1 (5XPNC1) has 70% longer replicative lifespan than the wild-type and some cells live for more than 70 divisions. Neither DR nor heat stress further increase the lifespan of the 5XPNC1 strain [12736687]. PNC1 deletion decreases chronological lifespan [17110466]. | Budding yeast |
| aakg-2 | AMP-Activated protein Kinase Gamma subunit 2 | aakg-2 overexpression extends mean, median, and maximum lifespan by 47, 45, and 35%. Overexpression of aakg-2 toegther with D. rerio ucp2 was non-additive with sDR [22737090]. | 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 |
