| LAT1 | — | LAT1 is suggested to play a role in lifespan extension of DR. Deleting LAT1 abolishes replicative lifespan extension induced by 0.5% and 0.05% glucose restriction. In contrast, overexpressing Lat1 extends replicative lifespan, and this lifespan extension was not further increased by 0.5% glucose restriction. Similar to DR, replicative lifespan extension by LAT1 overexpression largely requires mitochondrial respiration [17200108]. Overexpressing LAT1 extends lifespan (20% mean lifespan increase) and this lifespan extension is not further increased by DR. Similar to DR, lifespan extension by Lat1 overexpression largely requires mitochondrial respiration indicating mitochondrial metabolism plays an important role in DR. Interestingly, LAT1 overexpression does not require the Sir2 family to extend lifespan. Lat1 is also a limiting longevity factor in non-dividing cells in that overexpressing LAT1 extends cell survival during prolonged culture at stationary phase. | 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 |
| HAP4 | Heme Activator Protein 4 | Overexpression of HAP4 from the ADH1 promoter extends lifespan of PSY316 strain approximately 40% under growth conditions favoring fermentation (2% glucose). Overexpression of HAP4 increases replicative lifespan, but is non-additive with 0.5% glucose restriction in lifespan extension. Lifespan extension by HAP4 overexpression requires SIR2 [12124627]. HAP4 deletion suppresses replicative lifespan extension to 30% and 33% on 0.1% glucose and on elimination of non-essential amino acids, respectively [20178842]. HAP4 overexpressing cells demonstrate a transcriptional response resembling cells undergoing diauxic shift, consume more oxygen, and exhibit increased Sir2-dependent transcriptional silencing at telomeres and rDNA [12124627]. | Budding yeast |
| GUT2 | Glycerol UTilization 2 | Overexpression of GUT2 extends replicative lifespan by 25% and does not synergize with 0.5% glucose restriction [18381895]. | Budding yeast |
| AAT1 | Aspartate AminoTransferase 1 | Overexpression of AAT1 extends replicative lifespan by 25% and does not synergize with 0.5% glucose restriction [18381895]. | Budding yeast |
| MXR1 | peptide Methionine sulfoXide Reductase 1 | Deletion of MXR1 (alias MsrA) decreases by 25% and overexpression slightly increases the replicative lifespan [15141092]. Deletion of MXR1 decreases replicative lifespan [19049972]. MXR1 deletion decreases replicative lifespan on either glucose or lactate as carbon source [20799725]. Although deletion or overexpression of MXR2 (alias MsrB) has no effect under normal growth conditions, the simultaneous deletion of MXR1 and MXR2 reduces the lifespan by 63% [15141092]. | 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 |
| BMH2 | Brain Modulosignalin Homologue 2 | Overexpressing 14-3-3 protein, Bmh2, significantly extends median chronological lifespan by activating stress response [19805817]. | Budding yeast |
| SIR4 | Silent information regulator 4 | Deletion of SIR4 results in 20-25% reduction of lifespan [10521401]. SIR4 deletion mutants exhibit loss of silencing at the silent mating type loci [3297920] and telomeres [1913809] and have slightly elevated level of rDNA marker loss [10521401]. The short lifespan of a SIR4 mutant is probably due to the simultaneous expression of a and alpha mating-type information, which indirectly causes an increase in rDNA recombination and likely increases the production of extrachromosomal rDNA circles. Lifespan reduction by SIR4 deletion is suppressed by preventing mating type heterozygosity (co-expression of MATa and MATalpha). The sir4-42 mutation extends lifespan of by more than 30% and is semidominant in Bx1-14c strain which carrys a C-terminal truncation of MPT5/UTH4. sir4-42 extends lifespan by preventing recruitment of the SIR proteins to HM loci and telomeres, thereby increasing their concentration at other chromosomal regions. Expression of only the carboxyl terminus of SIR4 interferes with silencing at HM loci and telomere, which also extends lifespan [7859289]. Both Sir3 and Sir4 relocate to the nucleolus in the sir4-42 mutant background, dependent upon MPT5 and YGL023. sir4-42 has no effect on lifespan in a UTH4 wild-type strain background [9150138]. sir-4-42 results in constitutive localization of SIR3 to the rDNA. Lifespan extension by sir4-42 is likely due to increased dosage of SIR2 at the rDNA [10521401]. | Budding yeast |
| MPT5 | — | Overexpression of MPT5 from the ADH promoter extends replicative lifespan by about 20% in W303R [11805047] and by 25% in PSY142 [9150138], whereas the deletion of MPT5 shortens lifespan by about 50% [9150138; 7859289]. MPT5 deletion decreases average chronological lifespan by 50%, which is rescued to the wild-type level by PKC1 overexpression [17172436].
MPT5 mutants are temperature sensitive [7845352], hypersensitive to mating pheromone [9154842], and null mutants exhibit increased silencing at telomeres and decreased rDNA silencing [9584615]. Deletion of MPT5 is synthetical lethal with mutation of either SWI4, SWI6, or CCR4 in an ssd1-d background [11805047]. MPT5 overexpression suppresses the temperature phenotype of POP2 mutant [9504907]. MPT5 is required for relocalization of the SIR complex to the nucleolus in sir4-42 strain [7859289]. | Budding yeast |
| MDH1 | Malate DeHydrogenase 1 | Overexpression of MDH1 extends replicative lifespan by 25% and does not synergize with 0.5% glucose restriction [18381895]. | 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 |
| OSH7 | OxySterol binding protein Homolog 7 | Overexpression of OSH7 extends mean replicative lifespan. PERG6-OSH7 does not extend the maximum lifespan significantly [Xia et al., unpublished].
Deletion of the CC domain of Osh7 (Perg6-OSH7-ORD) greatly shortens the lifespan. Deletion of the Osh7's CC domain decreases lifespan (Perg6-OSH7-ORD) shortens the lifespan [Tang et al., personal communication].
Osh7 interacts with the late endosome ATPase Vps4 by their C-terminal coiled-coil (CC) domain. | Budding yeast |
| ERG2 | ERGosterol biosynthesis 2 | Overexpression of ERG2 with the promoter of ERG6 (Perg6-ERG2) extends replicative lifespan and this effect was overlapping with moderate DR, because DR can not extend the lifespan of this mutant [Tang et al., unpublished].
Perg6-ERG2 does not extend the lifespan significantly on normal medium, but it reverses the effect of DR. DR greatly shortens the lifespan of Perg6-ERG2 mutants. Perg6-ERG2 shortens the lifespan of nyv1 deletion mutations [Xia et al. unpublished].
Deletion of OSH5 greatly shortens the lifespan of Perg6-ERG2. SIR2 overxpression extends the lifespan of Perg6-ERG2 [Xia et al. unpublished]. | Budding yeast |
| PEP4 | carboxyPEPtidase Y-deficient 4 | Overexpression of vacuolar aspartyl protease (PEP4) extends chronological lifespan by increasing cytosolic polyamine and S-adenosylmethionine (SAM) levels. Deletion of PEP4 results in both apoptotic and necrotic cell death during chronological aging [21593793]. PEP4 is not DR-essential [18690010]. | Budding yeast |
| AVT1 | Amino acid Vacuolar Transport 1 | Overexpressing or deleting AVT1 is sufficient to extend or shorten replicative lifespan, respectively [23172144].
Overexpression of AVT1 prevents mitochondrial dysfunction, prevents alterations in mitochondrial structure and ΔΨ of aged cells even through the vacuolar acidity is reduced in these cells. AVT1 overexpression extends the mean, median and maximum replicative lifespan by 28, 28, and 22%, respectively [23172144].
Deletion of AVT1 accelerates the development of age-induced mitochondrial dysfunction without effecting the kinetics of vacuolar acidity decline and prevents the suppression of mitochondrial dysfunction by VMA1 and VPH2 overexpression without affecting vacuolar acidity. AVT1 deletion decreases mean, median and maximum replicative lifespan by 21, 22, and 12%, respectively [23172144]. | Budding yeast |
| VPH2 | Vacuolar pH 2 | Overexpression of VPH2 increases the levels of assembled V-ATPase at the vacuolar membrane, increases vacuolar acidity and suppresses age-induced mitochondrial dysfunction of aged cells (17 or 18 cell divisions) which requires the V-ATPase activity. VPH2 overexpression significantly increases mean, median and maximum replicative lifespan by 23, 25 and 34%, respectively [23172144]. | Budding yeast |
| VMA1 | Vacuolar Membrane Atpase 1 | Overexpression of VMA1 increases vacuolar acidity and suppresses age-induced mitochondrial dysfunction of aged cells (17 or 18 cell divisions) which requires the V-ATPase activity. VMA1 overexpression significantly increases mean, median and maximum lifespan by 39 - 45%, 39 - 48% and 50 - 60%, respectively. DR (0.5% glucose restriction) does not further increase the lifespan of VMA1 overexpression strain [23172144].
| Budding yeast |
| SOD2 | SuperOxide Dismutase 2 | SOD2 deletion decreases replicative lifespan by 72% [17460215]. SOD2 deletion decreases chronological lifespan [21076178]. Deletion of SOD2 decreases chronological lifespan in wild-type and abolishes chronological lifespan extension in sch9Delta mutants as well as decreases chronological lifespan in cyr1:mTn mutants [12586694]. Combined overexpression of SOD1 and SOD2 extends chronological lifespan by 30% in EG103 strain [12586694].
SOD2 deletion mutants are hypersensitive to oxygen and grow poorly in ethanol [10222047]. | Budding yeast |
| old-2 | Overexpression Longevity Determinant | Overexpression of old-2 increases slightly, although statistically significant mean and maximum lifespan by 19 and 44% [9768365]. | Nematode |
| ctl-1 | CaTaLase 1 | ctl-1 loss of function shortens lifespan to 77% of wild-type animals. ctl-1 mutants accumulate fluorescent material faster than wild-type, indicating accelerated aging [12610632]. ctl-1 mutation prevents lifespan extension by daf-2 or clk-1. Mutation of ctl-1 reudces catalase activty by 50% [10335847].
All these results have been retracted. | Nematode |
| hsb-1 | Heat Shock factor Binding protein | hsb-1(cg116) mutation at 20 degree Celsius extends mean, 75%ile, and maximum lifespan by 57-60%, 52-59%, and 37-69%. | Nematode |
| daf-18 | Abnormal DAuer Formation | daf-18 is required for complete dauer formation. Overexpression increases adult lifespan in individual tissues [16153634]. daf-18 mutation partially suppresses the lifespan extension of age-1 and daf-2 mutants. daf-18 mutants are defective for dauer formation and form some dauer-like larvae when starved [7789761; 8601482]. | Nematode |
| hsp-16.1 | Heat Shock Protein | Overexpression of the hsp-16 loci enhances stress resistance and extends mean lifespan by 11% at 20 degree Celsius. Lifespan extension by hsp-16 overexpression requires daf-16 [12882326]. | Nematode |
| hsp-16.49 | Heat Shock Protein | Overexpression of the hsp-16 loci enhances stress resistance and extends mean lifespan by 11% at 20 degree Celsius. Lifespan extension by hsp-16 overexpression requires daf-16 [12882326]. | Nematode |
