| Hells | helicase, lymphoid specific | A hypomorphic deletion of helicase domains 3, 4 and part of 2, leads to expression of a C-terminal truncated Hells protein causing an extremely short lifespan. with 60% of homozyogous mutants dying after birth and remaining 40% surviving up to seven weeks (around 25 days) [15105378].
Hells disruption results in genomic hypomethylation, de-repression of silenced genes, and premature aging, characterized by decreased proliferation, increased replicative senescence, and altered expression of Bmi-1 and p16INK4a. Hells mutant exhibit significant hypoglycemia, low birth weight and growth retardation, and signs of premature aging such as greying hair and balding, reduced fat deposition, unstable gait, cachexia, and kyphosis [15105378]. | House mouse |
| Arntl | aryl hydrocarbon receptor nuclear translocator-like | Arntl knockout mice display symptoms of premature aging including a shorter lifespan, sarcopenia, cataracts, less subcutaneous fat, and organ shrinkage [16847346]. | House mouse |
| Atm | Ataxia telangiectasia mutated homolog (human) | Atm-deficient mice are viable, retarded in growth, infertile (male produce no mature sperm and female no gametes), display neurological dysfunction, and exhibit severe defects in T cell maturation while going on to develop thymomas [8917548; 8689683]. The majority of mutant mice rapidly develop thymic lymphomas and die before 4 months of age [8843194].
Cells of Atm(-/-) mice exhibit slow growth also in culture and premature senescence, telomeres are extensively shortened in multiple tissues [8689683].
Mice mutant for Atm and Terc display progressive multi-organ system compromise and features of accelerated aging [12540856]. | House mouse |
| 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 |
| Igf1 | Insulin-like growth factor 1 (somatomedin C) | Cardiac specific overexpression of Igf1 results in a 23% increase in median lifespan, though no increase in maximum lifespan [17973971]. | 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 |
| Mcm2 | minichromosome maintenance deficient 2 mitotin (S. cerevisiae) | Conditional knockouts with reduced expression develop normally but lifespan is greatly reduced with most animals living 10-12 weeks accompanied by deficiencies in the proliferative cell compartments of several tissues and increased cancer incidence. | House mouse |
| Atr | Ataxia telangiectasia and Rad3 related | Deletion of Atr in young adults eliminates 80-90% of proliferating cells and results in several age-related phenotypes accompanied by a depletion of stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity [18371340].
Atr mutant mice (so called Seckle mice) exhibit high levels of replicative stress during embryogenesis, when proliferation is widespread, but this is reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice display accelerated aging, which is further aggravated in the absence of p53. Seckel mice die in less than half a year, exhibit pancytopenia, cachexia and signs of premature aging, including hair graying, kyphosis, osteoporosis, accumulation of fat in the bone marrow, decreased density of hair follicles and thinner epidermis [19620979]. | House mouse |
| Brca1 | Breast cancer 1 | Deletion of Brca1 causes senescence in mutant embryos and cultured cells and tumorigenesis and signs of premature aging in adults [12533509]. Brca1 heterozygous appear to have shortened lifespan with 70% of tumor incidence. Lymphoma, but not ovarian and mammary gland tumors, occurs commonly in these animals. After a whole-body exposure to ionizing radiation, Brca1 heterozygous mice have a 3-5-fold higher incidence to ovarian tumors, but not lymphoma, when compared with Brca1(+/+) mice [17420720]. | 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 |
| Fxn | frataxin | Disruption results in reduced lifespan, increased oxidative stress, impaired respiration, and the development of hepatic tumors [16278235]. | House mouse |
| Efemp1 | Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 | Efemp1 knockout mice exhibited an early onset of aging-associated phenotypes including a 20% shorted median lifespan and 30% shorter maximum lifespan, decreased body mass, lordokyphosis, reduced hair growth, and atrophy [17872905]. | House mouse |
| Fgf23 | Fibroblast growth factor 23 | Fgf23 knockouts have a short lifespan and display premature aging-like symptoms including kyphosis, muscle wasting, osteopenia, emphysema, uncoordinated movement, atherosclerosis, and atrophy of the intestinal villi, skin, thymus, and spleen [16436465].
Lack of Fgf23 activities results in extensive premature aging-like features and early mortality of Fgf-23(-/-) mice, while restoring the systemic effects of FGF-23 significantly ameliorates these phenotypes, with the resultant effect being improved growth, restored fertility, and significantly prolonged survival of double mutants [18729070]. | House mouse |
| Ghr | Growth hormone receptor | Ghr knockouts (the so called Laron mice) are dwarfs with significantly extended lifespan by 40-50% [12933651]. Ghr-/- mice are significantly longer lived as Ghr+/+ or Ghr+/- mice (by 40-50%) in both females and males [10875265; 19370397]. 30% DR fails to affect overall survival, average or median long-lifespan of Growth hormone receptor knockout (GHRKO) mice and increased maximal lifespan only in females. Insulin sensitivity in GHRKO mutants is greater than in wild-type and is not further increased by DR [16682650]. Intermittent fasting also fails to extend the long lifespan of GHRKO mice [19747233]. Lifespan of mice with a deletion in the Ghr gene live almost 5 years [21123740]. In C57BL/6J this mutation increases life expectancy by 16 to 26% depending on gender [12933651] and in mice of mixed genetic background the increases amounted to 36-55% [9371826]. Serum levels of GH are elevated in mutant mice [9371826] and mutants are smaller than wild-type. IGF-1 and IGFBP-3 levels are also reduced in Ghr mutant mice [10875265]. The age-associated decline in memory retention is delayed in Ghr mutants [11336996]. Overexpression of a growth hormone antagonist (a mutated growth hormone that competes with the endogenous one) has no effect on lifespan [12933651]. | 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 |
| Nudt1 | nudix (nucleoside diphosphate linked moiety X)-type motif 1 | hMTH1-Tg mice express high levels of the hMTH1 hydrolase that degrades 8-oxoGTP and 8-oxoGTP and excludess 8-oxoguanine from both DNA and RNA.
hMTH1-overexpresing mice have significantly lower steady-state levels of 8-oxoguanine in both nuclear and mitochondrial DNA of several organs, including the brain. hMTH1 overexpression prevents the age-dependent accumulation of DNA 8-oxoguanine that occurs in the wild-type mice. These lower levels of oxidized guanines are associated with increased longevity and hMTH1-Tg animals live significantly longer than their wild-type littermates [23648059].
| 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 |
| Lmna | lamin A | Homozygous mice display signs of premature ageing, including a marked reduction in growth rate and death by 4 weeks of age. | 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 |
| Pten | phosphatase and tensin homolog | Increasing gene dosage via homogeneous and moderate overexpression, while retaining its normal pattern of tissue expression of Pten increases mean, median and maximum lifespan in both females and males. Mean lifespan is extended by 18% (males), 11% (females) and 14% (both). Median lifespan in males, females and both increases by 12%, 16% and 12%, respectively [22405073]. Transgenic Pten mice carrying the additional genomic copies of Pten are protected from cancer and present a significant extension of lifespan that is independent of their lower cancer incidence. Pten(g) mice have an increased energy expenditure and protection from metabolic pathologies [22405073].
PTEN promotes oxidative phosphorylation and decreases glycolysis. PTEN aslo upregulates UCP1 expression in brown adipocytes, which enhances their nutrient burning capacity and decreases adiposity and associated pathologies [23245767]
| House mouse |
| Irs2 | insulin receptor substrate 2 | Irs2 brain-specific knockout mice were overweight, hyperinsulinemic, glucose intolerant, yet more active and lived up to 18% longer. | House mouse |
| Kl | Klotho | Klotho disruption results in infertility and signs of premature ageing such as a short lifespan, arteriosclerosis, skin atrophy, osteoporosis, and emphysema. Klotho overexpression leads to lifespan extension [9363890]. Klotho is highly expressed in brain and kidney [10631108]. The circulating form of Klotho binds to a cell-surface receptor and represses intracellular signals of insulin and IGF1. Perturbing insulin and IGF1 alleviates the aging-like phenotypes in Klotho-deficient mice [16123266]. kl/kl mice initially develop normally but exhibit growth retardation starting at 3-4 weeks of age. Their average lifespan is 61 days (none more than 100 days). These mice gradually become inactive, with reduced stride length, atrophic genital organs, thymus atrophy, arteriosclerosis (medial calcification and intimal thickening), ectopic calcification in arterial walls, osteroposis, skin atrophy, impaired maturation of gonadal cells, emphysema, reduced growth hormone-producing cells in the pituitary gland, slight hypercalcemia, and hyperphosphatemia [9363890]. kl/kl mice have decreased insulin production and increased insulin sensitivity [11016890]. | 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 |
| 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 |
| Cav1 | caveolin, caveolae protein 1 | Knockout mice are viable and fertile but exhibit an approximately 50% reduction in lifespan probably due to a combination of pulmonary fibrosis, pulmonary hypertension, and cardiac hypertrophy [14690422]. | House mouse |
