| 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 |
| Kl | Klotho | Klotho disruption results in infertility and signs of premature ageing such as a short lifespan, arteriosclerosis, skin atrophy, osteoporosis, and emphysema. Klotho overexpression leads to lifespan extension [9363890]. Klotho is highly expressed in brain and kidney [10631108]. The circulating form of Klotho binds to a cell-surface receptor and represses intracellular signals of insulin and IGF1. Perturbing insulin and IGF1 alleviates the aging-like phenotypes in Klotho-deficient mice [16123266]. kl/kl mice initially develop normally but exhibit growth retardation starting at 3-4 weeks of age. Their average lifespan is 61 days (none more than 100 days). These mice gradually become inactive, with reduced stride length, atrophic genital organs, thymus atrophy, arteriosclerosis (medial calcification and intimal thickening), ectopic calcification in arterial walls, osteroposis, skin atrophy, impaired maturation of gonadal cells, emphysema, reduced growth hormone-producing cells in the pituitary gland, slight hypercalcemia, and hyperphosphatemia [9363890]. kl/kl mice have decreased insulin production and increased insulin sensitivity [11016890]. | House mouse |
| 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 |
| Bub1b | budding uninhibited by benzimidazoles 1 homolog, beta (S. cerevisiae) | Bub1b hypomorphic mutation decreases median lifespan by 60% (from 15 to 6 months) and such mutant mice that procude low levels of the protein are prone to aneuplody and develop many phenotypes suggestive of accelerated aging, including short lifespan, growth retardation, sarcopenia, lordokyphosis, progressive bilateral cataracts, substantial loss of sub dermal adipose tissue, spinal kyphosis, muscle atrophy, reduced dermal thickness and decreased wound healing [15208629; 17272762; 16781018; 18516091].
Moreover, there is a pronounced increase in senescent associated Beta-galactosidase expression in late generation Bub1b mutant mice, indicative of increased rate of cellular senescence. Homozyogous knockout of Bub1b results in lethality, while heterozygous animals exhibit no aging phenotypes [15208629].
Sustained high-level expression of BubR1 preserves genomic integrity and reduces tumorgenesis (even in the presence of genetic alterations that strongly promote aneuplodization and cancer, such as oncogenic Ras) and extends the lifespan and delays age-related deterioriation and aneuploidy in several tissues [23242215].
BubR1 overabundance exerts its protective effect by correcting mitotic checkpoints defects [23242215].
BubR1 expression level declines with age in various tissues [15208629; 17272762; 16781018].
The median and maximum lifespan of mice with a nonsense mutation 2211insGTTA in BubR1 is significantly reduced. BubR1(+/GTTA) mice develop several aging-related phenotypes at an accelerated rate, including catarct formation, lordokyphosis, skeletal muscle wasting, impaired exercise ability, and fat loss. Further BubR1(+/GTTA) mice develop mild anaplodies and exhibit enhanced growth of carcinogen-induced tumors [Wijshake et al. 2012].
| House mouse |
| GLaz | Glial Lazarillo | Overexpression of GLaz results in increased resistance to hyperoxia (100% O2) and a 29% extension of mean lifespan under normoxia. Lifespan was also extended 30-60% under starvation [16581512]. Loss-of-function mutation of GLaz which decreases its expression of GLaz results in shorter lifespan and decreased resistance to oxidative stress in males [16581513]. | Fruit fly |
| 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 |
| Atg8a | Autophagy-related 8a | Mutations in Atg8a results in reduced lifespan and increased sensitivity to oxidative stress while enhanced expression in older fly brains extends average adult lifespan by 56% and promotes resistance to oxidative stress [18059160].
Atg8a mutation reduces the maximum lifespan by 25% under starvation conditions [17617737].
Loss-of-function mutation in Atg8a reduces mean lifespan by 11 - 25% and maximum lifespan by 3 - 22% [17435236]. | Fruit fly |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| cst-1 | Caenorhabditis STE20-like kinase 1 | Knockdown of cst-1 shortens lifespan and accelerates tissue aging while its overexpression extends lifespan and delays aging in a daf-16-dependent manner [16751106]. | Nematode |
| 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 |
| 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 |
| lin-4 | abnormal cell LINeage 4 | A loss-of-function mutation in lin-4 shortens lifespan and accelerated tissue ageing while overexpressing lin-4 extends lifespan by redarding aging [16373574].
lin-4 is regulated by DAF-16 in L1 arrest. | 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 |
