| Akh | Adipokinetic hormone | Knockdown of the adipokinetic hormone (Akh) by RNAi (with an RU486-inducible and ubiquitously expressing Actin 5C-GS Gal4 strain) does not by itself affect lifespan, but significantly inhibits DR-dependent increase in lifespan across a range of yeast concentrations in both females and males. While control females and males exhibit a 113%/22% increase in lifespan under DR, upon Akh inhibition there was a significant reduction in lifespan extension with DR (52%/5%). Global Akh knockdown reduces starvation resistance by 24% upon DR, but no significant change upon AL. Also Akh RNAi repressed the DR-dependent increase in cold-stress resistance. Fat body and neuronal-specific inhibition of Akh by using RU486-inducible S(1)106-GS-Gal4 and Elav-GS-Gal4 enhancer traps, respectively, does not reduce lifespan extension upon DR. But, muscle-specific inhibition of Akh using RU486-inducible muscle enhancer trap (Mhc-GS-Gal4) reduces the DR-dependent increase in lifespan. While control exhibit a 47.2% lifespan extension, animals with muscle-specific Akh inhibition fails to result in any increase upon DR (i.e. completely blocked the DR lifespan extension). Muscle-specific Akh inhibition diminishes the increase in triglyceride synthesis and breakdown present normally under DR. A significant reduction in lifespan extension also occurs with a noninducible muscle driver (Mhc-Gal4). Controls on DR exhibit significant higher levels of spontaneous activity compared to Akh RNAi-inhibited animals at all ages. Akh inhibition reduces the protective effect of DR on age-related decline in muscle function/activity [22768842].
Fat-body specific Akh RNAi results in increased spontaneous activity and a small but significant increase in lifespan upon AL [22768842].
Overexpression of Akh in a ubiquitousness manner enhances fat metabolism (significant increase in triglyceride synthesis and breakdown under AL), spontaneous activity (148% on AL and 154% on DR), and lifespan on AL (33%). However, despite and increase in movement under DR, lifespan is not increased under a restricted diet [22768842]. | Fruit fly |
| 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 |
| 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 |
| aakg-2 | AMP-Activated protein Kinase Gamma subunit 2 | aakg-2 overexpression extends mean, median, and maximum lifespan by 47, 45, and 35%. Overexpression of aakg-2 toegther with D. rerio ucp2 was non-additive with sDR [22737090]. | Nematode |
| AAT1 | Aspartate AminoTransferase 1 | Overexpression of AAT1 extends replicative lifespan by 25% and does not synergize with 0.5% glucose restriction [18381895]. | Budding yeast |
| 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 |
| 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 |
| BMH2 | Brain Modulosignalin Homologue 2 | Overexpressing 14-3-3 protein, Bmh2, significantly extends median chronological lifespan by activating stress response [19805817]. | Budding yeast |
| 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 |
| 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 |
| Pka-C1 | cAMP-dependent protein kinase 1 | PKA-overexpressing flies (hsPKA*/+) have an about 30% extended maximum lifespan [17369827]. | Fruit fly |
| PEP4 | carboxyPEPtidase Y-deficient 4 | Overexpression of vacuolar aspartyl protease (PEP4) extends chronological lifespan by increasing cytosolic polyamine and S-adenosylmethionine (SAM) levels. Deletion of PEP4 results in both apoptotic and necrotic cell death during chronological aging [21593793]. PEP4 is not DR-essential [18690010]. | Budding yeast |
| CKIepsilon | casein kinase I epsilon | A mutation called tau, if homozygous, shortens the circadian period (by 20%), increases metabolic rate (by 20%), and increases lifespan by 14-16% under conditions of constant darkness [12054192].
Male and female wild-type hamsters are heavier than homozygous mutants throughout the entire lifespan, and heterozygous mutants have intermediate weight [12054192]. | Syrian hamster |
| CAT | catalase | Overexpression of human catalase targeted to mitochondria (MCAT) extends mean and maximum lifespan by about 20% in mice. Inactivation of aconitase in heat mitochondria and mitochondrial damage is also reduced in long-lived CAT mutant mice [15879174].
The MCAT strain has a reduced severity of age-dependent arteriosclerosis and increased genomic stability, as indicated by an decrease in oxidative stress and mitochondrial deletions in heart and muscle tissues. Median and maximum lifespan in increased about 17 - 21% [16144468].CAT was not found to be associated with longevity [15472150]. | Human |
| ctl-1 | CaTaLase 1 | ctl-1 loss of function shortens lifespan to 77% of wild-type animals. ctl-1 mutants accumulate fluorescent material faster than wild-type, indicating accelerated aging [12610632]. ctl-1 mutation prevents lifespan extension by daf-2 or clk-1. Mutation of ctl-1 reudces catalase activty by 50% [10335847].
All these results have been retracted. | 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 |
| 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 |
| 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 |
| cher | cheerio | Overexpression of cher from a doxycycline-inducible promoter results in a 7 - 9% increase in mean lifespan (in PdL x rtTA; Oregon-R x rtTA) [12620118]. | Fruit fly |
| Cct1 | CTP:phosphocholine cytidylyltransferase 1 | Overexpression of Cct1 from a doxycycline-inducible promoter results in a 6 - 8% increase in mean lifespan (in the PdL x rtTA; Oregon-R x rtTA strain) [12620118].
Cct1 exhibits a non-coding region difference unique to animals under experimental evolution selected for longevity and is upregulated in head of animals that were selected for longevity at all ages beyond the day of eclosion [23106705]. | Fruit fly |
| 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 |
| Mt2 | DNA methyltransferase 2 | Overexpression of Dnmt2 extends mean and maximum lifespan [15533947]. | 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 |
| ImpL2 | Ecdysone-inducible gene L2 | Lmp-L2 over-expression, ubiquitous or restricted to DILP-producing cells and/or gut and fat body, extends lifespan even if induced at adult onset [21108726]. Overexpression of ImpL2 increases mean and maximum lifespan by 15% and 23%, respectively. Lifespan is reduced when Impl2 is strongly over-expressed throughout the adult by the conditional GS driver, act-GS-GAL4 or da-GS-Gal3, while restricted over-expression of the ImpL2 in fat cells by using S106-GS-Gal4, which increases mRNA level about 6-fold extends lifespan in both sexes [22366109]. mRNA for Impl2 was strongly elevated in sterile, long-lived flies [18434551]. | Fruit fly |
