| Prx5 | Peroxiredoxin 5 | Prx5 overexpression causes an increase in mean and median lifespan under normal conditions. It also leads to a small increase in maximum lifespan.
dprx5(-/-) null mutants are comparatively more susceptible to oxidative stress, have higher incidence of apoptosis, and a shortened mean lifespan, but thee is no significant difference in maximum lifespan (10% survival) [21826223]. | Fruit fly |
| mir-246 | — | Mutating mir-246 decreases mean and maximum lifespan by 12%, while its overexpression increases mean and maximum lifespan by 6 and 5 - 14%, respectively [21129974]. | Nematode |
| mir-71 | — | Loss and gain-of-function of mir-71 decreases and increases lifespan, respectively [21129974]. mir-71 mutants have a reduced lifespan with 40% decrease in mean lifespan, while extra copies of mir-71 extend the lifespan with an increase in lifespan by 15 - 25% [22482727],
Loss of mir-71 function suppresses the long lifespan of glp-1(e2141) mutants [22482727],
During adulthood mir-71 is strongly expressed in the intestine, body wall muscles and neurons. mir-71 is upregulated in aging adults [22482727], | Nematode |
| 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 |
| Hsp22 | Heat shock protein 22 | Overexpression of mitochondrial Hsp22 in all cells or specifically in motorneurons (using GAL4/UAS binary system) increases life lifespan by 32% and resistance to oxidative stress [19948727; 20036725].
Ubiquitous or a targeted expression of Hsp22 within motorneurons increases the mean lifespan by more than 30%. Hsp22 shows beneficial effects on early-aging events since the premortality phase displays the same increase as the mean lifespan [14734639].
Animals that do not express Hsp22 (due to a transposition into its transcriptional starting site) have a 40% decrease in lifespan, exhibit a 30% decrease in locomotor activity and are sensitive to mild stress [20036725].
Doxycyline-regulated overexpression of Hsp22 makes animals more sensitive to heat and oxidative stress as well as reduces the mean lifespan by up to 21%, particularly at higher culture temperature [15491684].
Hsp22-promoter driven reporter overexpression reduces mean and maximum lifespan [19420297].
Histone deacetylase inhibitor Trichostatin A (TSA) extends the lifespan of *Drosophila melanogaster* by promoting the hsp22 gene transcription, and affecting the chromatin morphology at the locus of hsp22 gene along the polytene chromosome [15346199].
| Fruit fly |
| pck-1 | Phosphoenolpyruvate CarboxyKinase 1 | RNA interference of pck-1 during the adulthood significantly shortens lifespan of both wild-type and eat-2 mutants. RNAi knockdown of pck-1 from hatching cases larval lethality. Overexpression of pck-1 greatly increases content of PEPCK-C, markedly induces enzyme activity and significantly increases mean, 75%ile, and maximum lifespan by 19-23%, 17-22%, and 21% [22810224]. | Nematode |
| 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 |
| sptf-3 | Specificity Protein Transcription Factor 3 | RNAi against sptf-3 decreases mean and maximum lifespan by 20 - 28% and 28%, respectively. sptf-3 RNAi in the adulthood decreases the mean and maximum lifespan by 23 and 37% [23144747]. sptf-3 overexpression extends lifespan [18059442]. | Nematode |
| Thor | — | Null mutation in Thor (alias d4E-BP) causes a significant decrease in longevity (-25% median lifespan in males). Thor is strongly upregulated during starvation. foxo and Thor null mutants are compromised in stress resistant. Stress resistance of foxo null mutants is rescued by Thor overexpression [16055649]. Thor is upregulated on the protein level in a foxo-independent manner upon DR, while it is transcriptional induced in a foxo-dependent fashion by starvation. Thor null mutants cancel out DR-induced lifespan extension, because mutants exhibit a diminished change in lifespan when nutrient conditions were varied. Ubiquitously expression of Thor rescued DR response in females and males. Thor null mutants have a wild-type similar reduction in egg production upon DR. Ubiquitously overexpression of wild-type Thor causes no change under AL, but an activated allele (with more than 3-fold increased binding activity to delF4E) significantly extends lifespan of females (weak allele) and females as well as males (strong allele). Mean lifespan is extended by 11 to 40%. Median lifespan of males and females is enhanced by by 11 and 22%, respectively. Maximum lifespan is extended by 16 and 18% for males and females, respectively. Under DR (0.25% YE) there is no lifespan extension, beyond the effect of DR alone, in all (wild-type, weak and strong) Thor alleles [19804760].
Lifespan of animals with increased Pten and 4E-BP activity in muscle exhibit and extended mean and maximum lifespan by 20% and 15.8% [21111239]. | Fruit fly |
| Sirt6 | sirtuin 6 (silent mating type information regulation 2, homolog) 6 (S. cerevisiae) | Sirt6 knockout mice develop signs of premature ageing including a short lifespan [16439206].
Overexpression of Sirt6 in male mice lengthens the median lifespan by 9.9-14.5% and maximum lifespan by 13.1-15.8% [22367546].
Mice without Sirt6 have a higher risk of gastrointestinal cancers. SIRT6 dampens cancer growth by repressing aerobic glycolysis (i.e. conversion of glucose to lactate; a major feature of cancer cells). Loss of Sirt6 increases the number, size and aggressiveness of tumors. Sirt6 loss leads to tumor formation even without activation of oncogenes. Transformed SIRT6-deficient cells exhibit increased glycolysis and tumor growth. Sirt6 inhibits the transcriptional activity of the oncogene Myc via corepression [23217706]. Sirt6 also protects against diet-induced obesity [http://www.biocompare.com/Life-Science-News/127206-Anti-Aging-Gene-Identified-As-Tumor-Suppressor-In-Mice-Research-Finds/].
| House mouse |
| trx-1 | ThioRedoXin 1 | Thioredoxins regulate many cellular redox processes. trx-1 is mainly associated with neurons and is expressed in ASJ ciliated sensory neurons and to some extent also on the posterior-most internal cells. trx-1 reduces protein disulfides in the presence of a heterologous thioredoxin reductase. trx-1 null mutant display reduced mean and maximum lifespan [16387300]. Mutants with a deletion in the trx-1 gene display a decrease in lifespan and are sensitive to oxidative stress [16324156]. trx-1 overexpression extends lifespan in wild-type but not in eat-2 mutants. trx-1 deletion completely suppresses the lifespan extension caused by eat-2 mutation, but only partially suppresses that by daf-2 or osm-5 mutations. Ectopic expression of trx-1 in ASJ neurons (but not in the intestine) in trx-1 mutants rescues the lifespan-extension conferred by eat-2 mutation. trx-1 overexpression extends lifespan of wild-type but not in eat-2 mutants. trx-1 deletion almost completely suppresses lifespan extension induced by dietary deprivation (DD). DD upregulates trx-1 expression in ASJ neurons. DR activates trx-1 in ASJ neurons which in turn triggers a trx-1-dependent non-cell autonomous mechanism to extend adult lifespan [21334311].
| Nematode |
| Cisd2 | CDGSH iron sulfur domain 2 | Cisd2 knockouts expire premature ageing and reduced lifespan [19451219]. A persistent level of Cisd2 achieved by transgenic expression extends mean, median and maximum lifespan without any apparent deleterious side effects [22661501]. | House mouse |
| 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 |
| 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 |
| 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 |
| LAG2 | Protein involved in determination of longevity | Deletion of LAG2 in haploid SP1 strain does not affect growth, but results in a 50% decrease in the mean and maximum replicative lifespan. When LAG2 is overexpressed, the mean and maximum replicative lifespan is extended by about 36% and 54%, respectively. Overexpression induced at generation 12 similarly increases replicative lifespan [8760941]. | 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 |
| Sod2 | Superoxide dismutase 2 (Mn) | RNA interference of Sod2 results in increased oxidative stress and early-onset mortality in young adults [12456885]. Overexpression of Sod2 by 5-115% decreases lifespan by 4-5% without any compensatory changes in metablic rate, level of physical activity, or the levels of other antioxidants (Sod, Cat, and glutathione) [10545213]. Targeted overexpression of Sod2 in motor neurons alone extends lifespan by 30% [11113599]. Induced overexpression of Sod2 in adult animals extends lifespan up to 37% [12072463]. Overexpression of catalase in combination with SOD2 has no added benefit for lifespan [12072463]. Animals overexpressing SOD2 or catalase do not exhibit a decrease in metabolism as measured by oxgen consumption [12072463].
Sod2 overexpression results in a 20% increase in mean and maximum lifespan [18067683]. | Fruit fly |
| 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 |
| SOD1 | SuperOxide Dismutase 1 | The overexpression of Sods, mitochondrial Sod2 and cytosolic CuZnSod (Sod1), in combination delays the age-dependent reversible inactivation of mitochondrial aconitase, a superoxide-sensitive enzyme, and extends chronological lifespan by 30% [12586694]. Deletion of SOD1 decreases replicative lifespan by 40% [17460215]. Overexpression of SOD1 with CCS1 levuates the level of Cn, Zn-Sod activity and increased chronological lifespan. However overexpression of SOD1 without high cooper or simultonous overexpression of CCS1 shortened both chronological and replicative lifespan [15659212]. Overexpression of SOD1 has no effect on replicative lifespan [10224252]. Deletion of SOD1 shortens replicative lifespan by approximately 40%. The magnitude of the decrease in lifespan does not appear to dependent on oxygen concentration in the atmosphere [12020810]. Deletion of SOD1 shortens replicative lifespan [10547026]. Deletion of SOD1 shortens replicative as well as chronological lifespan [10222047].
Cells with a deletion of SOD1 exhibit a profound defect in entry into and survival during stationary phase (i.e. chronological lifespan) in the W303-B strain [8647826; 10222047], which is partially suppressed by expression of human Bcl-2 [9199172].
Hypersensitivity to oxygene and significantly decreased replicative lifespan of SOD1 deletion can be ameliorated by exogenous ascorbate. If acorbate's negative effects of auto-oxidation are prevented by exchange of medium, ascorbate prolongs mean and maximum replicative lifespan in the atmosphere of air and pure oxygene [15621721].
SOD1 deletion causes sensitivity to hyperoxia as well as methionine and lysine auxotrohies [9199172].
| Budding yeast |
| 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 |
| 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 |
| NF1 | Neurofibromin 1 | NF1 mutants have a shortened lifespan and exhibited increased vulnerability to heat and oxidative stress as well as reduced mitochondrial respiration and elevated ROS production. Overexpression of NF1 increases mitochondrial respiration and reduced ROS production. It increases mean lifespan by 49% in males and 68% in females and maximum lifespan by 38% in males and 52% in females. It also improved reproductive fitness [17369827]. | Fruit fly |
| 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 |
