| bchs | blue cheese | Loss of function mutation in bchs results in a 40-45% decrease in mean lifespan and is associated with age-related neurodegenerative phenotype with reduced CNS size and altered morphology as well as accumulation of insoluble ubiquinated proteins and amyloid precursor-like proteins along with an increase in neuronal apoptosis. No pronounced developmental defects were observed and young adults have normal behaviours, indicating that the bchs gene is essential for normal adult survival and longevity [12598614].
bchs mutation reduces mean lifespan by 28 - 54% and maximum lifespan by 24 - 46% [17435236].
Alfy (autophagy-linked FYVE protein) is the conserved human bchs homolog [15292400]. | Fruit fly |
| Bmcp | Mitochondrial uncoupler | Bmcp knockout flies live longer on low-calorie diets, have a decreased fertility, and gain less weight on high-calorie diets. Bmcp (ucp5) knockout mutants live longer than wild-type on low-calorie diets, but no longer on starvation or high-calorie diets. Ectopic neuronal expression of Bmcp transgene rescues starvation sensitive phenotype of Bmcp knockout mutants [16387864]. | Fruit fly |
| chico | Insulin receptor substrate-1 | Mutation in chico extends mean, median, and maximum lifespan by 56%, 48%, and 42% in homozygotes and 44%, 36%, and 35% in heterozygotes. chico mutation produces dwarf, long-lived females at normal nutrition. Male heterozygous live 13% longer than wild-type, but male homozygous have a shortened lifespan [11292874]. Wild-type and chico mutant females have similar peak lifespan under DR, but the food concentration at which these are achieved is shifted to higher amounts. chico mutation induces a state equivalent to submaximal, DR-induced slowing of aging [11951037]. chico heterzoygous females have a reduced fecundity and homozygous recessive mutants are sterile. chico heterozygous mutants are resistant to starvation but not oxidative stress or temperature stress [11292874]. | Fruit fly |
| dnc | dunce | cAMP phosphodiesterase-deficient dunce mutants have an extended maximum lifespan by about 70% [17369827]. | Fruit fly |
| mld | molting defective | Female, but not male, heterozygous mutants display a 42% increase in mean lifespan at 29 degrees Celsius. DTS-3 +/- female adults exhibit a 50% reduced ecdysone titer and reduced fertility [12610309]. Female, but not male, heterozygoutes also exhibit a temperature-dependent increase in starvation resistance. | Fruit fly |
| EcR | Ecdysone receptor | Mutant heterozygotes in EcR live on mean 40%-50% longer than controls [12610309; reviewed in 12610294]. Homozygous mutants in EcR are inviable. The developmental time and weight of EcR+/- mutants is the same as control, but resistance to temperature, oxidative stress, and starvation is increased in heterozygotes [12610309]. | Fruit fly |
| egm | enigma | Mutation in egm confers resistance to oxidative stress and extends the lifespan [16434470]. | Fruit fly |
| Indy | I'm not dead yet | Flies heterozygotic for a disruption in Indy gene have extended mean (87-92%) and maximum (45%) lifespan. Homozygotes for the disruption show only a 10 - 20% increase in mean lifespan [11118146]. Heterozygous insertion of a p-element in the non-coding region of Indy locus leads to a reduction in Indy mRNA expression and causes a significant median lifespan extension in male and female by about 29% and 34%, respectively. At normal or high calorie conditions Indy heterozygote mutants have a significant lifespan extension, but under low calorie conditions, Indy heterozygous mutants have minimal median lifespan extension. Reduction of calorie content from high to normal calorie condition results in 19% decline in Indy mRNA and from normal to low calorie condition results in additional 9% decrease in Indy mRNA. Reduction of calorie content from high to normal calorie conditions in heterozygous Indy mutants leads to 20% reduction in Indy mRNA expression without any additional decrease upon further reduction to low calorie food. Maximum lifespan extension is associated with Indy mRNA levels between 25 - 75% of normal. Long-lived heterozygous Indy mutants on high-calorie food and normal wild-type on low-calorie food have several phenotypes in common: 50 - 60 % reduced mRNA expression levels of Ilp2, Ilp3 and Ilp 5; similar high percentage of anti-FOXO-positive nuclei in fat body cells; higher sensitivity to starvation; do not gain weight; similar decrease in triglycerides and fat storage; normal food intake [19470468].
Mutations in Indy dramatically extend lifespan without a loss in fertility, physical activity, flight velocity or metabolic rate [11118146; 12626742]. Indy encodes a high-affinity dicarboxylate/citrate plasma membrane transporter found most abundantly in adult fat body, oenocytes and midgut cells, the primary sites of intermediary metabolism [12391301]. Indy mutation alters metabolism in a manner similiar to DR and mutants have several phenotypes with long-lived DR files in common, including decreases insulin-like signaling, lipid storage, weight gain, and resistance to starvation, and an increase in spontaneous physical activity [19470468].
Of the Indy206 and Indy302 mutation only one of the two has lower mRNA levels and both do not extend lifespan of female flies in any genetic background. In original genetic background only Indy mutation associated with altered RNA expression extends the lifespan of males. This effect is abolished by back-crossing into standard out-bred genetic backgrounds and is associated with an unidentified locus on the X chromosome. Original Indy line with long-lived males is infected by the cytoplasmic Wolbachia. Longevity of Indy males disappear after tetracycline clearance of this endosymbiont [17571923]. | Fruit fly |
| InR | Insulin-like 1 receptor | Mutations in InR (InRE19/InRp5545 transheterozygous) result in dwarf females with extended lifespan of up to 85% and dwarf males with reduced late age-specific mortality (although no significant change in lifespan) [11292875]. InrGC25/InrE19 transheterozygous animals are short-lived an exhibit an elevated rate of age-independent mortality [11292874].
Natural allelic variation in InR are associated with variation in lifespan [15013662; 20074316]. | Fruit fly |
| mth | methuselah | Mutants in mth display approximately 35% and 36% increase in average and maximum lifespan as well as enhanced resistance to various forms of stress (including starvation, high temperature, and dietary paraquat) [9794765].
Reduced expression of mth targeted only to the insulin-producing cells of the brain is sufficient to extend lifespan and to enhance oxdative stress resistance [23121290].
IPC-targeted overexpression of β-arrestin alone mimics the longevity phenotype of reduced mth signaling [23121290]. | Fruit fly |
| Orco | Odorant receptor co-receptor | Loss-of-function mutation in Orco (alias Or83b) results in olfactory defects, altered adult metabolism, enhanced stress resistance, and life-extension. Fully fed female homozygous Or83b null mutants exhibit a 56% increase in median lifespan and a 30% increase in maximum lifespan. Males are also significantly longer-lived, though to a smaller degree and maximum lifespan is not extended. Heterozygous mutants of both sexes show an intermediate longevity. Lifespan of homozygous Orco null mutants is further increased by DR, but the relative increase in median and mean longevity is significantly greater when mutants were maintained in well-fed conditions [17272684].
| Fruit fly |
| ovo | — | The dominant ovoD1 allele extends female lifespan by approximately 50%. It does not synergize or prevent life-extension caused by chico [10617470; 11292874].
ovoD1 mutants are sterile [Mevel-Ninio et al. 1991]. | Fruit fly |
| p53 | — | Overexpression of wild-type p53 during adult life has no significant effect on lifespan. Expression of dominant-negative versions of p53 in adult neurons extends lifespan by 58% in females and by 32% in males and increases resistance to genotoxic stress and resistance to oxidative stress, but not to starvation or heat stress, while not affecting egg production or physical activity.
Dominant negative p53 expression cancels out lifespan extension effect of DR, low calorie-food (5% SY). Muscle or fat body specific expression of a dominant negative form of p53 as well as globally lack of p53 decreases lifespan [16303568]. Loss of p53 activity slightly shortens the lifespan. Mutants that lack p53 survive well up to 50 days, but mortality rate increases relative to wild-type at later ages. p53 mutant animals are extremely sensitive to irradiation [12935877].
Expression of dominant-negative (DN) form of p53 in adult neurons, but not in muscle or fat body cells, extends median lifespan by 19% and maximum lifespan by 8%. The lifespan of dietary-restricted flies is not further extended by simultaneously expressing DN-DMp53 in the nervous system, indicating that a decrease in Dmp53 activity may be part of the DR lifespan-extending effect. Selective expression of DN-Dmp53 in only the 14 insulin-producing cell (IPCs) in the brain extends lifespan to the same extent as expression in all neurons and this lifespan extension is not additive with DR [17686972].
| Fruit fly |
| puc | puckered | Heterozygous loss-of-function mutations in puc (either pucA241.1 or pucE69) significantly extend median and maximum lifespan and increase resistance to oxidative stress. Heterzyogosity for puc only modestly extends lifespan in animals carrying a hypomorphic allele of the JNK kinase hep [14602080].
puc heterzyogotes do not differ signficantly from wild-type for body size, reproductive activity or developmental timing, but exhibit increased resistance to oxidative stress and starvation [14602080]. | Fruit fly |
| Rpd3 | Histone deacetylase Rpd3 | Males heterozygous for hypomorphic (partial loss-of-function) or null mutation of Rpd3 have a lifespan extension of 33% and 41 - 47%, respectively. Females heterozygous for a hypomorphic allele have a 52% increase in lifespan, but females carrying a null mutation have only modest increase in maximum lifespan (but not median lifespan). Longevity increases to the same extent in wild-type under low-calorie diet and rpd3 mutants fed normal diet. DR fails to further increase lifespan of rpd3 mutants. DR leads to a moderate but significant down-regulation of Rpd3, analogous to decrease obtained in heterozygotes carrying rpd3 mutation. rpd3 mutants fed normal food and wild-type fed low-calorie increase Sir2 expression two-fold [12459580]. | Fruit fly |
| S6k | RPS6-p70-protein kinase | Ubiquitous overexpression of a dominant-negative form of S6k (alias dS6K) increases mean lifespan by 22% and overexpression of a constitutively active form of S6k decreases mean lifespan by 34% at 29°C. Overexpression of a dominant-negative form of S6k protects mutants from deleterious effects of rich food, as if mimicking the effect of DR [15186745]. | Fruit fly |
| sun | Stunted | sun mutations increases lifespan and resistance to oxidative stress [15133470] | Fruit fly |
| Surf1 | surfeit gene 1 | Surf1 knockdown results in larval lethality. However, knockdown in the central nervous system (CNS) not only bypasses the larval lethality but it results in an increase in maximum lifespan of about 20-30% [16172499]. | Fruit fly |
| Tor | Target of rapamycin | Expression of a dominant-negative form of Tor extends lifespan [15186745]. Ubiquitious overexpression of dTOR with the da-GAL4 driver of UAS-dTOR(FRB) which contains the 11kDA FKB12-rapamycin binding domain led to a mean and maximum lifespan increase of 15% (24%) and 29% at 29°C and of 50% (26%) and 13% at 25°C, respectively [15186745].
Overexpression of the dominant-negative form of Tor specifically in the fat and muscle tissues is sufficient to extend the mean and maximum lifespan by 24 and 19%, respectively [15186745].
Overexpression of UAS-dTOR(WT) or UAS-dTOR(TED) prevents eclosion to adulthood [15186745]. | Fruit fly |
| bwa | brain washing | bwa (alias Dacer) inactivation increases Drosophila pre-adult development time and anti-oxidative stress capacity. Mean lifespan is increased by 16% in females, by 21% in males and by 19% in total. Maximum lifespan of females, males is also extended by 20 and 12%, respectively [20112046]. | Fruit fly |
| Ilp2 | Insulin-like peptide 2 | Flies with an ablation of median neurosecretary cells (which eliminates Ilp2 expression) exhibit a significant increase in mean and maximum lifespan over that of control flies and an increase to oxidative stress and starvation. The mutants also exhibit increased storage of lipid and carbohydrate, reduced fecundity, and reduced tolerance of heat and cold [15708981]. The median and maximum lifespan of females is increased by 33.5% and 40%, respectively. In males the median and maximum lifespan is increased by 10.5% and 27%, respectively [15708981].
Ilp2 RNA interference results in a 24% to 47% increase in median lifespan [19005568].
Ilp2 is transcriptional down-regulated in long-lived mutants. Ilp2 null mutants are significant longer-lived with a 8-13% longer median lifespan, but have a normal DR response. Ilp2 Ilp3 Ilp5 triple null mutants fail to have a normal response to DR. Their response is right shifted, with mutants shorter-lived compared to wild-type on low but longer-lived on high yeast concentrations [20195512]. | Fruit fly |
| pex1 | peroxin 1 | Mutation of the promoter region of pex1(S4868), results in lower expression levels and increases lifespan in males and females by 16% and 13%, respectively. pex1 mutation increases mean and maximum lifespan and males/females by 27-23/14-19% and 0-15%, respectively [22509016]. | Fruit fly |
| pex13 | peroxin 13 | Mutation of pex13(KG04339), located in its promoter region, results in lower gene expression and increased lifespan by around 16% and 13% in males and females. pex13 mutation increases mean and maximum lifespan by 23-27/14-19% and 11%, respectively [22509016]. | Fruit fly |
| CG5389 | — | RNAi of complex V subunit CG5389 results in increased mean longevity under standard laboratory food conditions (3% yeast) in males. RNAi started from the development results in a mild lifespan increase in both sexes (3-11% in females and 3-8% in males). Post-developmental RNAi and silencing limited to neurons has variable effects with reduction in lifespan of up to 9% [19747824]. Under rich media conditions CG5389 knockdown throughout development and adulthood increases mean lifespan by 26% and abolished the lifespan extension by DR (started in the adulthood) in males. Suppression of CG5389 only during the adulthood either via RNAi by tub-GS or via oligomycin (a specific inhibitor of complex V) feeding prevents an increase in longevity under DR (started in the adulthood) in males [19968629]. | Fruit fly |
| aPKC | atypical protein kinase C | Insertion of a P-based vectors in the structural part of aPKC increase male and female lifespan [22661237]. | Fruit fly |
