| Xrcc6 | X-ray repair complementing defective repair in Chinese hamster cells 6 | XRCC5 and XRCC6 double knockout mice show decreased lifespan and signs of premature ageing without increase cancer incidence. | House mouse |
| Xrcc5 | X-ray repair complementing defective repair in Chinese hamster cells 5 | Deletion results in signs of premature ageing such as osteopenia, atrophic skin, hepatocellular degeneration, and age specific mortality. | House mouse |
| XPA | Xeroderma pigmentosum, complementation group A | Mutant mice exhibit symptoms of premature ageing, including reduced lifespan, osteoporosis and kyphosis, osteosclerosis, early greying, cachexia, and infertility. | House mouse |
| Ucp2 | uncoupling protein 2 (mitochondrial, proton carrier) | Overexpression in hypocretin neurons results in mice with elevated hypothalamic temperature and reduction of core body temperature and a 12% increase in median lifespan in males and 20% increase in females. | House mouse |
| Trp63 | Transformation related protein 63 | Heterozygous Trp632 mutant mice have a shortened lifespan (by 21.5%) and display features of accelerated aging [16107615].
The decreased longevity in Trp63(+/-) mice is almost identical to that of Trp53(+/m) mice in which enhanced Trp53 activity provides resistance to spontaneous tumors while simultaneously accelerating aging [16107615]. Trp63(+/-) are not susceptible to spontaneous tumors [16107615]. | House mouse |
| Trp53 | Transformation related protein 53 | Mice heterozyogous for an allele of p53 that removes the 5' portion of the protein demonstrate decreased cancer, permature aging phenotypes, and shortened lifespan in the mixed inbred C57BL/6â129/Sv background. It has been proposed that the this allele of p53 results in increased activity/overexpression [11780111]. Decreased activity of Trp53 results in increased cancer and decreased apoptosis. Mutant mice with activated Trp53 display enhanced resistance to spontaneous tumours and signs of premature ageing including reduced lifespan, osteoporosis, organ atrophy and a diminished stress tolerance [11780111]. However, super-p53 mice generate by a transgenic copy of a large genomic segment containing an intact and complete copy of p53 have an ehanced response to DNA damage, are significantly protected from cancer and had no indication of accelerated aging [12426394]. super-Ink4a/Arf/p53 mice have a synergic protection against cancer and delayed aging [Workshop RoSyBa 2011]. | House mouse |
| Top3b | Topoisomerase (DNA) III beta | Homozygous disruption of Top3b results in a normal development but a shorter lifespan (by approximately 70%) accompanied by lesions in multiple organs in C57BL/6 [11331780].
Yeast Top3 physically interacts with Sgs1 [7969174]. Human TOP3A interacts with BLM [10734115; 10728666] and both TOP3A and TOP3B interact with RECQ5 [10710432]. | House mouse |
| Tert | Telomerase reverse transcriptase | Overexpression of telomerase results in a high cancer incidence but also a modest mean (10%) and maximum lifespan extension accompanied by a lower incidence of some age-related degenerative diseases, in particular those related to kidney function and germline integrity [15688016]. Mice genetically modified to express telomerase lived 40% longer and do not develop cancer. Overexpression of Tert in mice engineered to be cancer-resistant by means of ehanced expression of p53, p16 and p19ARF (Sp53/Sp16/SARF/TgTERT) decreased telomere shortening with age, delayed aging and increases mean and median longevity by 40% [19013273]. Re-activation of telomerase in a model of premature aging caused by accelerated telomere shortening (duo to telomerase deficiency) was enough to revert some age-associated phenotypes [21113150].
Mice treated with an adeno-assoicated virus vector expressing TERT at the age of one lived 24% longer on average and those treated at the age of two, by 13%. Maximum lifespan of the mice treated at 1 and 2 years was also extended by and 13% and 20%, respectively. AAV9-mTERT treated mice also had improved health, delayed onset of age-related diseases (like osteoporosis and insulin resistance) as well as improved readings in ageing indicators like neuromuscular coordination [22585399].
The gene therapy consists of a single injected via tail vein and achieved a transduction efficiency of 20-50%. Already 1 month after treatment, the treated mice at both age groups had longer telomeres and a decrease in the short telomeres in multiple tissues, while the controls exhibit an increase in short telomerase. In contrast to their control littermates at 3 and 8 months post-treatment the blood of most of the AAV9-treated mice at 1 year had no decrease or exhibit even a net increase in average telomere length and had also no increase or even a marked decrease in percentage of short telomeres with time. Thus, the therapy achieved in perhipheral blood leukocytes a prevention of telomere shortening. Treated mice had lower leves of fasting insulin, improved glucose tolerance and better homeostatic model assessment. Two years old treated mice had higher IGF1 levels. Treated mice at both ages had improved memory scores. AAV9-mTERT treatment increased cyclinD1 positive cells in various tissues. Upon AAV9-mTERT treatment levels of p16 decreased in most organs (with exception of heart). The metabolic and mitochondrial decline in 2 years old mice treated was not as apparent as in controls [22585399]. | House mouse |
| Terf2 | telomeric repeat binding factor 2 | Overexpression results in signs of premature ageing. | House mouse |
| Surf1 | surfeit gene 1 | Knockout mice displayed a prolonged lifespan of about 20%. | House mouse |
| Stub1 | STIP1 homology and U-Box containing protein 1 | Knock-out mice exhibited a deregulation of protein quality control accompanied by a short lifespan and accelerated age-related pathophysiological features. | House mouse |
| Slc25a4 | solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 4 | Knockouts exhibited a shortened lifespan and increased hydrogen peroxide production and in some tissues. | House mouse |
| Shc1 | SHC (Src homology 2 domain containing) transforming protein 1 | Heterozyogus and homozygous Shc1 knockout mice have an 7% and 28% increase in mean lifespan, respectively [10580504].
p66shc-/- cells are more resistant to apoptosis induced by hydrogen peroxide and UV light. p66shc-/- mice aremore restante to oxidative stress induced by paraquat [10580504]. | House mouse |
| Rae1 | RAE1 RNA export 1 homolog (S. pombe) | Haploinsufficiency of Bub3 and Rae1, but not haploinsufficiency of either gene by itself, reduces lifespan by 12% and appears to accelerate ageing. | House mouse |
| Prop1 | Prophet of Pit1, paired-like homeodomain transcription factor | Knockouts of Prop1 are dwarf (hence called the Ames dwarf mice) but live approximately 1 year longer than controls. Mean lifespan of males and females is extended by 49 and 68%, respectively [8900272]. Ames dwarf mice are small due to retarded post-natal growth with a body size of one-third upon maturation into adulthood) [10838701; 8900272] and have primary pituitary deficiency consisting of the absence of, or extreme reduction in, anterior pituitary cells which produces growth hormone, prolactin and thyroid-stimulating hormone, and consequently a deficiency in these hormones [8565826; 8900272]. Levels of IGF1 is also extreme low in Ames dwarf mice [8900272] and they maintain lower body temperature at rest and during stress, which is on average 1.6 degree Celsius lower [10497963]. df/df mice tend to be steril [14173795]. | House mouse |
| Prdx1 | Peroxiredoxin 1 | Homozygous Prdx1 knockout mice have a lifespan significant shorter than +/+ and +/- littermates and develop severe haemolytic anaemia and several malignant cancers (starting at about 9 months of age) [12891360] | House mouse |
| Ppm1d | protein phosphatase 1D magnesium-dependent, delta isoform | Knockout mice are resistant to spontaneous tumors but show a modest reduction in lifespan and reduced body weight. | House mouse |
| Polg | Polymerase (DNA directed), gamma | Mice with a proof-reading-deficient version of Polg display an increased amount of mtDNA mutations (by 3 to 5-fold) and signs of premature ageing including a reduced lifespan, weight loss, reduced subcutaneous fat, alopecia, kyphosis, osteoporosis, anaemia, reduced fertility, and heart enlargement. Median lifespan of homozyous Polg mutant knock-in mice is 48 months [15164064]. | House mouse |
| 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 |
| Pou1f1 | POU domain, class 1, transcription factor 1 (Pit1, growth hormone factor 1) | Snell dwarf mutation (Pit1dw) due to knockout of Pou1f1 results in a dramatic lifespan extension. The mean, median and maximum lifespan is increased by 40-50% for Snell dwarf (Pit1dw/Pit1dw) DW/J females, and 25-50% for dwarf DWC3F1 males and females with a compound heterozygous Pit1dw/Pit1dw-J genotype. Although, Snell dwarf (Pit1dw/Pit1dw) DW/J males exhibit aspects of delayed senescence, their median lifespan is by about 25% shorter, probably due to the affects of housing conditions [11718806]. Mice homozygous for loss-of-function mutations at Pit1 locus have a mean and maximum lifespan extension over 40%. Mutant dwJ/dw animals exhibit delays in age-dependent collagen cross-linking and in six age-senstive indices of immune system status. Pituitary transplantation into dwarf mice does not reverse the lifespan extension effect. Male Snell dwarf mice become obese and exhibit proportionately high leptin levels in old age [11371619]. | House mouse |
| Pck1 | phosphoenolpyruvate carboxykinase 1, cytosolic | Overexpression of Pck1 in skeletal muscle results in an increased number of mitochondria, markedly increase in activity, and extended lifespan by 30%. Transgenic mice ate 60% more than controls but had half the body weight and 10% of the body fat [17716967; Hakimi, Berger and Hanson, unpublished]. Pck1 overxpression leads to increased storage and utilization of fatty acids in muscle for energy purposes and mutants store up to 5-times more triglyceride in their skeletal muscle, and exhibit increased levels of physiological activity [18394430]. | House mouse |
| Pawr | PRKC, apoptosis, WT1, regulator | Mice overexpressing the pro-apoptotic protein domain were resistant to tumours. Transgenic animals showed normal fertility, viability, and ageing, though they were slightly longer-lived possibly because of the cancer-resistance. | House mouse |
| Pappa | Pregnancy-associated plasma protein A | Genetic deletion of PAPPA extended mean and maximum lifespan by 30-40% and reduced cancer incidence with no reduction in food intake or secondary endocrine abnormalities. | House mouse |
| Nos3 | nitric oxide synthase 3, endothelial cell | Knockout males exhibited premature death and age-related cardiac dysfunction but not females. | House mouse |
| Neil1 | nei endonuclease VIII-like 1 (E. coli) | Knockout mice develop severe obesity, dyslipidemia, fatty liver disease, increased levels of DNA damage in the mtDNA, and have a tendency to develop hyperinsulinemia. | House mouse |
