| 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 |
| Sirt1 | sirtuin 1 (silent mating type information regulation 2, homolog) 1 (S. cerevisiae) | Whole-body deletion of Sirt1 in the adulthood results in mice which are seemingly normal in every way. When mice were given low doses of resveratrol after Sirt1 was disabled, there were no discernible improvement in mitochondrial function or any parameter, while mice with normal Sirt1 function given reservatrol showed dramatic increases in energy, mitochondrial biogenesis and function, AMPK activation and increased NAD+ levels in skeletal muscle. When mice lacking Sirt1 were given low doses of reserveratrol, AMPK was unaffected. When doses were significantly increased in these mice, AMPK was activated in a SIRT1-indepent manner, but still no benefit to mitochondrial function resulted [22560220]. Sirt1 overexpression mimicks the effect on reservatrol on mitochondrial function, but failed to extend lifespan [22560220].
SIRT1 knock-out mouse embryonic fibroblasts (MEFs) have a significant greater replicative capacity in culture. p19ARF levels are significantly reduced in SIRT1 knock-out MEFs [16054100].
Sirt1-null mice do not exhibit lifespan extension upon Dietary Restriction [18335035].
Sirt1 is required for high-magnitude circadian transcription of several core clock genes. It deacetylates Per2, Arntl and histones of clock-controlled genes [18662546].
SIRT1 directly [21187328] and indirectly [20450879] prevents telomere shortening. | House mouse |
| Vegf | Vascular endothelial growth factor A | Vegf exhibits rhythmic expression in the liver [17360649]. Vegf expression is affected by the circadian organization of molecular clockwork. Levels of Vegf mRNA fluctuate in a circadian fashion. Period2 and Cryptochrome inhibit the Vegf promoter [14612524]. | 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 |
| Terc | telomerase RNA component | Telomerase null mice exhibit age-dependent telomere shortening and shortened lifespan with succeeding generations. Median lifespan is reduced by 26% in G6 Terc(-/-) mice compared to wild-type or G1-G3 Terc(-/-) (18 months vs. 24 months). G6 Tec(-/-) display hair greying, hair loss, and ulcerative skin lesions, as well as impaired response to wound healing and hematoitopitic ablation, and an increased incidence of cancer [10089885]. Cells from Terc(-/-) mice (G4 and upward) exhibit chromosomes lacking detectable teloemre repeats, aneuplody, and end-to-end fusions [9335332]. | House mouse |
| Rgn | regucalcin | Survival among make animals lacking Rgn (alias SMP30) is 50% at 180 days compared to 100% among controls [N. Maruyama, unpublished data].
SMP30-/- mutant mice are indstuguishibale form their SMP30+/+ littermates in terms of development and fertilization capacity [12368201]. However, -/- mice were more susceptible to liver injury after treatment with anti-FAS antibody. SMP30-/- hepatocytes cultures in vitro are more susceptible to apoptosis induced by tumor-necrosis factor (TNF-alpha) plus actinomycin D (ActD) than SMP30+/+ hepatocytes.
| House mouse |
| Srf | Serum Response Factor | SRF is activated by the daily variations of a blood signal, resulting in significant changes in the structure and size of live cells throughout the course of the day [23374345].
Daily variations of plasma signal cyclically stimulates SRF. SRF is solicited in an antiphasic manner in humans and rats, a fact that is linked to their activity, diurnal and nocturnal, respectively. SRF activation is accompanied by a remodeling of the cellular "skeleton", resulting in morphological change in cells based on their activity [23374345].
| House mouse |
| Sod2 | superoxide dismutase 2, mitochondrial | Sod2(-/-) mice are born smaller, pale and less vigorous, and die with 7-10 days. The major problems are dilated cardiomyopathy, accumulaiton of lipid in various tissues particularly liver and skeletal muscle, and metabolic acidosis [7493016]. In another strain background Sod2(-/-) mice have severe anemia, degeneration of neurons in the basal ganglia and brainstem, and progressive weakness, fatigue, and cricling behavior [8790408]. Treatment of Sod(-/-) mice with superoxide dismuate/catalase mimetics (EUK-8, EUK-134, or EUK-189) partially rescues the short lifespan (mean lifespan 14-28 days) and other phenotypes [9462746].
Two-fold overexpression of Sod2 in young (4-6 months) and old (26-28 months) throughout the life results in decreased lipid peroxidation, increased resistance against paraquat-induced oxidative stress, and decreased age-related decline in mitochondrial ATP production, without any change on lifespan or age-related pathology [19633237].
Life-long reduction in MnSOD activity leads to increased levels of oxidative DNA damage and increase cancer incidience, but does not appear to affect aging. Sod2(+/-) mice that have a 50% reduction in MnSOD activity in all tissues throughout the life have increased oxidative damage as evidenced by significantly elevated levels of 8-oxo-2-deoxyguanosine in nuclear DNA (in all tissues) as well as in mitochondrial DNA (in lver and brain). Increased oxidative damage to DNA is associated with a 100% increase in tumor incidience in old Sod2(+/-) mice. However, mean and maximum lifespan of Sod2(+/-) and wild-type mice is identical. Biomarkers of aging, such as cataract formation, immune response, and formation of glycooxidation products carboxylmethyl lysine and pentosidine in skin collagen changes with age to the same extent in both wild-type and Sod2(+/-) mice.
Sod2(+/-);Gpx(-/-) animals exhibit no reduction in lifespan, despite increased levels of oxidative damage and neoplasms as well as tumorgenesis [19776219]. | 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 |
| 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 |
| Rgs16 | Regulator of G-protein signaling 16 | Rgs16 knockdown have shorter free-running period of locomotors activity rhythm and reduced total activity. Under daytime RF food-anticipatory activity is attenuated and phase-advance of rhythmic Per2 expression in liver and thalamus is diminished [21408016]. | House mouse |
| Cebpa | CCAAT/enhancer binding protein (C/EBP), alpha | 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 |
| 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 |
| — | Rapamycin | Rapamcyin increases mouse lifespan even when administrated late in life [19587680]. | House mouse |
| Prkaa1 | Protein kinase, AMP-activated, alpha 1 catalytic subunit | Prkaa1 hosphorylates Cryptochromes and leads to their degradation [19833968]. | House mouse |
| Fgf21 | Fibroblast growth factor-21 | Overproduction of Fgf-21 increases mean lifespan of males by 30% and that of females by 39% [23066506].
Mice overproducing Fgf21 are lean throughout their lives and remain lean even while eating slightly more than wild-type mice. Fgf21 overproducers tend to be smaller than wild-type mice and female mice were infertile. Although Fgf21 overproducers have significantly lower bone density than wild-type, Fgf21-abundant mice exhibit no ill effects from the reduced bone density and remain active into old age without any broken bones.
Fgf21 seems to provide its health benefits by increasing insulin sensitivity and blocking the growth hormone/insulin-like growth factor-1 signaling.
Fgf21 acts as a hormone, is secreted by the liver during fasting and helps the body to adapt to starvation.
| House mouse |
| Terf2 | telomeric repeat binding factor 2 | Overexpression results in signs of premature ageing. | 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 |
| 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 |
| MIR20A | microRNA 20a | Overexpression of MiR-20a in mouse embryonic fibroblasts induces senescence by lowering Lrf (a transcriptional repressor of the Mdm2 inhibitor p19ARF [15662416; 9529248]) protein levels and in turn increasing p19ARF levels [18596985]. | House mouse |
| Gh | Growth hormone | Overexpression of GH is associated wtih markedly reduced lifespan and various indices of premature aging [8100276]. Transgenic mice overexpressing bovine GH1 are bigger than controls and display signs of premature aging such as a shortened lifespan, glomerulosclerosis and glomerulonephritis, increased astrogliosis, and early onset of age-related changes in cognitive function [14583653]. | House mouse |
| Nfkbia | nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha | Overexpression of an endothelial dominant-negatvie I?B? gene prolonged the lifespan [22302838]. | House mouse |
| Gh | growth hormone 1 | Overexpression of a growth hormone antagonist (a mutated growth hormone that competes with the endogenous one) in mice has no effect on lifespan [12933651]. | 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 |
| Ercc2 | Excision repair cross-complementing rodent repair deficiency, complementation group 2 | Mutations in Ercc2 increases cancer incidence and appear to accelerate ageing. Homozyogus mutation of Ercc2 results in an extreme shortening (71%) of lifespan (mean lifespan = 7 months) relative to wild-type (mean lifespan = 24 months) [de Boer et al. 2002]. The shortened lifespan of the mutant mouse is accompanied by symptoms of premature aging including osteoporosis, early greying, cahexia, and infertility. It provides a mouse model for the britte hair disorder trichothiodystrophy (TTD) as it phenotypes include britte hair, UV sensitivity, and developmental defects [9651581]. | House mouse |
