| Sir2 | — | Overexpression of Sir2 (alias dSir2) extends lifespan by up to 57% and specifically median lifespan by 40-60%, whereas a decrease in Sir2 activity by mutation blocks the life-extending effect of caloric reduction or rpd3 mutations [15520384]. rpd3 mutants fed normal food and wild-type fed a low-calorie diet increase dSir2 expression two-fold [12459580]. Sir2 mutation does not reduce lifespan under AL. Ubiquitous Sir2 overexpression causes a 4-fold increase in Sir2 mRNA expression and an up to 57% increase in average lifespan (29% for females and 18% for males). A 10 - 20% increase in Sir2 mRNA levels causes no lifespan extension. High levels of Sir2 protein is found in nuclei of neurons and in nuclei and cytoplasm of fat body cells. Neuronal Sir2 overexpression extends average lifespan by 52% in females and 20% in males. Motor-neuronal specific expression fails to cause lifespan extension. Flies with no or with several decreased Sir2 gene function have no lifespan extension under DR. DR fails to cause further increase in lifespan or even reduces lifespan toward normal of Sir2 overexpression mutants. Mild Sir2 overexpression in the fat-body extends lifespan and reduces relative body fat content in both males and females [22661237].
Sir2 in the adult fat body regulates longevity in a diet-depending manner. A diet-dependent lifespan phenotype of Sir2 perturbations (both knockdown and overexpression) in the fat-body, but not in muscles, negates the effects of background genetic mutants. Sir2 knockdown abrogates fat-body dFoxo-dependent lifespan extension [23246004].
Decreased expression of Sir2 and Sir2-like genes in all cells causes lethality during development. Suppression of the Sir2 in neurons decreases the median lifespan by 10-30%, while ubiquitinous silinecing of the Sir2-like genes shortens lifespan. The effects are server at 28°C that at 25°C [17159295]. | Fruit fly |
| hebe | — | Adult-specific overexpression of hebe increases the lifespan by 5-30% and modulates late-age female fecundity. Female and male mean lifespan is up to 11% and 24% higher [19011900]. | Fruit fly |
| magu | — | Adult-specific overexpression of magu increases lifespan by 5-30% and modulates late-age fecundity [19011900]. | Fruit fly |
| Pten | — | Increased Pten and 4E-BP activity in muscles is extends the lifespan [21111239]. | 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 |
| 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 |
| Atg2 | Autophagy-specific gene 2 | Atg2 overexpression increases average female lifespan by 28% [18059160]. | Fruit fly |
| bam | bag of marbles | Bam mutants have an extended lifespan due to germ cell loss. Lifespan of females is on average up to 50% higher and that of males on average s up to 27.8% higher [18434551]. | Fruit fly |
| Pka-C1 | cAMP-dependent protein kinase 1 | PKA-overexpressing flies (hsPKA*/+) have an about 30% extended maximum lifespan [17369827]. | Fruit fly |
| Eip71CD | Ecdysone-induced protein 28/29kD | Overexpression of Eip71CD (alias MsrA) in nervous system extends the lifespan by up to 70%, increased resistance to oxidative stress, and delays the onset of senescence-induced decline in activity levels and reproductive capacity. Eip71CD is a downstream effector of foxo [22310715].
Mean and maximum lifespan is increased by up to 2-% in animals that overexpress Eip71CD [20655917]. | Fruit fly |
| Ef1alpha48D | Elongation factor 1alpha48D | Overexpression of Ef1alpha48D (transformed with a P-element vector and under control of hsp70 regulatory sequences) results in lifespan extension by 18-41%. The decrease in protein synthesis that accompanies aging is preceded by a decrease in EF-1 alpha protein and mRNA [2508089]. | Fruit fly |
| foxo | Forkhead box, sub-group O | foxo overexpression extends lifespan. Activation of foxo in the adult pericerbral fat body is sufficient for lifespan extension [15175753]. Overexpression of foxo in the adult adipose tissue alone prolongs lifespan [15192154; 15175753]. Limited activation of foxo reduces the expression of Drosophila insulin-like peptide dilp-2 synthesized in neurons and, represses endogenous insulin-dependent signaling in peripheral fat body [15175753]. foxo is not required for DR, but its activity modulates the response. foxo null mutants are highly and significantly shorter-lived than wild-type on all food dilutions apart from 0.1 SY and under starvation. foxo null mutants are not more sensitive to starvation than wild-type. foxo overexpression in adult fat body under normal nutritional conditions leads to extension of lifespan of females and causes a right shift of the response curve of lifespan to DR [18241326].
Overexpression of dFOXO in adult fat body increases median, by 21-33%, and maximum lifespan as well as lowers the age-specific mortality at all ages, in two independent experiments. Overexpression of dFOXO increases lifespan by lowering the whole mortality trajectory, with no effect on slope (similar to DR). Initiation of dFOXO expression at different ages increases subsequent lifespan with the magnitude of increase decreasing as the animals were put on RU486 (which activates the foxo transgene via UAS) at older ages. The effects of removal of dFOXO overexpression at different ages closely mirrored those of induction of expression and produce shortest lifespan observed in animals taken of RU486 at the earlier ages [17465980].
| Fruit fly |
| fh | frataxin homolog | Overexpression of fh in the mitochondria of female transgenic animals increases antioxidant capability, resistance to oxidative stress insults, and longevity [18258192]. | Fruit fly |
| Gclc | Glutamate-cysteine ligase catalytic subunit | Overexpression of Gclc extends mean and maximum lifespan by up to 50% [16148000]. | Fruit fly |
| Gclm | Glutamate-cysteine ligase modifier subunit | Overexpression of Gclm extends the mean lifespan by up to 24% [16148000]. | Fruit fly |
| GstS1 | Glutathione S transferase S1 | GstS1 overexpression increases the mean lifespan by 33% [18059160]. | Fruit fly |
| Gadd45 | growth arrest and DNA damage-inducible gene 45 | Gadd45 overexpression in the nervous system leads to a significant increase of lifespan without a decrease in fecundity and locomotor activity. The lifespan extension effect is more pronounced in males than in females. Additional maximum lifespan is also extended. The maximum lifespan is increased by 50% and 59% for females and males, respectively. The median lifespan is extended by 46 and 77% for females and males, respectively [22661237]. | 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 |
| Hsp26 | Heat shock protein 26 | Overexpression of Hsp26 (by the UAS/GAL4 system) increases stress resistance and extends the mean lifespan by 30% [15308776]. | Fruit fly |
| Hsp27 | Heat shock protein 27 | Overexpression of Hsp27 (by the UAS/GAL4 system) increases stress resistance and extends the mean lifespan by 30% [15308776]. | Fruit fly |
| Hsp68 | Heat shock protein 68 | Overexpression of Hsp68 extends modestly (by around 15%) median and maximum lifespan [14602080]. Hsp68 is activated by the JNK pathway and target gene of foxo [20976250].
There is a consistent and significant lifespan extension by 20% in both males and females when hsp68 is overexpressed in somatic cells. hsp68 overexpression using GMR-Gal4, and eye-specific driver that expresses Gal4 in salivary glands has no effects. Hsp78 overexpression using the weaker 5961FS driver moderately but significantly extends lifespan [20976250]. | Fruit fly |
| Hsc70-3 | Heat shock protein cognate 3 | Overexpression of Hsc70-3 increases average female lifespan by 27% [18059160]. | Fruit fly |
| INS | insulin | Expression of human insulin under an inducible heat shock promoter increases nematode lifespan by 25% and is also able to enhance the lifespan of daf-2 mutants [11274053]. INS was found to be associated with longevity [22406557; 19367319; 17989723; 19489743]. | Human |
| MTF-1 | Metal response element-binding Transcription Factor-1 | MTF-1 overexpression in either the peripheral nervous system or motorneurons extends both mean and maximum lifespan by 40% in males [18775584]. | Fruit fly |
| mys | myospheroid | mys mutants exhibit ameliorated age-related declines in locomotor activity and an increase in mean lifespan of 20% [14570233]. | Fruit fly |
