| Tsc1 | CG6147-PA Tuberous sclerosis complex genes 1 | Ubiquitously overexpression of UAS constructs (via the daughterless (da)-GAL-4 driver) containing dTSC1 extends mean lifespan at 29°C by 14% [15186745]. | Fruit fly |
| Cbs | — | Ubiquitous or neuron-specific transgenic overexpression of Cbs enhances longevity in fully-fed animals. Cbs RNAi partially abrogates increased lifespan by DR, but has no effect on fully fed animals. Cbs upregulation is required for increased lifespan under low-nutrient conditions. Response of male flies to DR is muted in comparison with females. Adult-specific ubiquitous expression of Cbs is sufficient to increase female mean and maximum lifespan by 12 - 43% and 10%, respectively. Males, whose lifespan is relatively less affected by DR, exhibite a smaller, but still significant increase in lifespan by 7% upon Cbs overexpression. Neuronal overexpression also increases lifespan, albeit modestly (approximately 12% mean and 15% maximum lifespan extension), whereas overexpression in the fat body and in the gut has no effect [21930912]. | Fruit fly |
| NDT80 | Non-DiTyrosine 80 | Transient overexpression of NDT80 rejuvenates old cells [21700873]. | Budding yeast |
| IME1 | Inducer of MEiosis 1 | Transient overexpression of IME1 resets the replicative lifespan of old cells back to that of young cells [21700873]. | Budding yeast |
| Plau | Plasminogen activator, urokinase | Transgenic mice (called alphaMUPA) overexpression Plau in many brain sites (including hypothalamus) consume (20%) less food, have a reduced body weight (by 20%) and length (by 6%), reduced temperature, and a prolonged lifespan (by 20%) [9060969].
alphaMUPA mice have reduced levels of blood sugar and smaller size and birth frequency compared to parental control [9060969] as well as a reduced body weight [10638529]. | House mouse |
| SNCA | synuclein, alpha (non A4 component of amyloid precursor) | Transgenic lines overexpressing either human wild-type or mutant (A53T) forms of the SNCA (alpha-synclein) gene under a pan-neuronal promoter live on average about 25% longer, even in weak (m577) and strong (e1370) daf-2 mutant backgrounds, and exhibited decreased pharyngeal pumping and egg-laying. Wild-type SNCA crossed into eat-2(ad1113) does not significantly effect lifespan compared to that of the background strain. Pumping rate in wild-type SCNA and A53T SCNA overexpression mutants were less than control already at day 1 of adulthood. The attenuation of lifespan exptesion by SNCA overexpression by growing on thick bacterial lawns, suggests that DR may explain some fo the effects on lifespan. SCNA overexpression increases average lifespan by 21.3% (wild-type) and 16.3% (A53T) [16782295].
Mutation of SCNA (alias alpha synclein) is associated with Parkinson's disease [9197268], which is characterized with resting tremor, rigidity bradykinesia and posural instability that are associated with selective neurodegeneration of the pigmented neurons in the brain stem (substantia nigra and locus coerues) and the presence of intracytoplasmic inclusion bodies (Lewy bodies) [Yamamura et al. 1973]. The mutated protein (Ala53Thr or Ala30Pro) may misfold, aggregate and resist degradation [11433374].SNCA was found to be associated with longevity [22912757]. SNCA was not found to be associated with longevity [22912757]. | Human |
| Spargel | — | Tissue-specific overexpression of dPGC-1 in stem and progenitor cells within the digestive tract of females flies extends the mean and maximum lifespan of females by up to 33% and 37%. Those mutants display a delay in the onset of aging-related changes in the intestine, leading to improved tissue homoeostasis in old flies [22055505]. | 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 |
| EXO1 | exonuclease 1 | The rs1776180 C allele in the promoter of EXO1 is significantly enriched in female Germans centenarians and this can be replicated in 445 female French centenarians. The C allele leads to the loss of binding site for the basic helix-loop-helix transcription factor E47, resulting in higher EXO1 expression [19698732].EXO1 was found to be associated with longevity [19698732]. EXO1 was not found to be associated with longevity [23770741]. | Human |
| 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 |
| TERT | telomerase reverse transcriptase | Telomerase-expressing cells (human foreskin fibroblasts, retinal pigment epithelial cells) maintain normal length of telomeres and continue to divide vigorously [9454332]. Cells expression telomerase have reduced staining for beta-galactosidase (a biomarker of cellular senescence) [9501072]. TERT expression is also able to prevent the accelerated replicative senescence observed in cells taken from Werner's patients [10615119].
A haplotype of TERT was correlated with both longer both longer telomere length and exceptional longevity. Mutations in TERT were overpresented in Ashkenazi centenarians [19915151].TERT was not found to be associated with longevity [22136229]. TERT was found to be associated with longevity [23562826]. | Human |
| 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 |
| sod-1 | SOD (superoxide dismutase) | sod-1 overexpression increases mean, median, and maximum lifespan by 32, 25, and 35% [22737090]. | Nematode |
| 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 |
| 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 |
| Sod1 | Superoxide dismutase | Simultaneous overexpression of catalase and Sod (alias Sod1) results in a one-third lifespan extension, a slower rate of mortality acceleration, and a delayed loss in physical performance, but neither has any effect on lifespan alone [8108730]. General overexpression of Sod (also known as Cu/ZnSOD) alone is sufficient to extend lifespan by up to 48%. Simultaneous overexpression of catalase with Cu/ZnSOD has no added benefit, presumably due to a pre-existing excess of catalase [9858546]. Sod1 reduction by knockdown or knockout blunts the lifespan extension by a high sugar-low protein diet, but not a low-calorie diet [22672579].
Sod mutant flies display infertility and a reduction in lifespan [2539600]. | Fruit fly |
| 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 |
| 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 |
| 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 |
| 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 |
| mtl-2 | MeTaLlothionein | RNA interference of mtl-2 extends lifespan by 20% in N2 rrf-3(pk 1426). mtl-2 is differentially transcribed in daf-16 and daf-2 RNAi animals [12845331]. | 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 |
| Cebpb | CCAAT/enhancer binding protein (C/EBP), beta | Replacing the Cebpa gene by Cebpb increases mean lifespan by about 20% [15289464]. C/ebpalpha(beta/beta) animals consume more food but weight less than controls [10982846], and have a slightly elevated body temperature (0.3-0.5 degree Celsius) [15289464]. | House mouse |
| 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 |
