| 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 |
| SNCA | synuclein, alpha (non A4 component of amyloid precursor) | Transgenic lines overexpressing either human wild-type or mutant (A53T) forms of the SNCA (alpha-synclein) gene under a pan-neuronal promoter live on average about 25% longer, even in weak (m577) and strong (e1370) daf-2 mutant backgrounds, and exhibited decreased pharyngeal pumping and egg-laying. Wild-type SNCA crossed into eat-2(ad1113) does not significantly effect lifespan compared to that of the background strain. Pumping rate in wild-type SCNA and A53T SCNA overexpression mutants were less than control already at day 1 of adulthood. The attenuation of lifespan exptesion by SNCA overexpression by growing on thick bacterial lawns, suggests that DR may explain some fo the effects on lifespan. SCNA overexpression increases average lifespan by 21.3% (wild-type) and 16.3% (A53T) [16782295].
Mutation of SCNA (alias alpha synclein) is associated with Parkinson's disease [9197268], which is characterized with resting tremor, rigidity bradykinesia and posural instability that are associated with selective neurodegeneration of the pigmented neurons in the brain stem (substantia nigra and locus coerues) and the presence of intracytoplasmic inclusion bodies (Lewy bodies) [Yamamura et al. 1973]. The mutated protein (Ala53Thr or Ala30Pro) may misfold, aggregate and resist degradation [11433374].SNCA was found to be associated with longevity [22912757]. SNCA was not found to be associated with longevity [22912757]. | Human |
| TXN | thioredoxin | Overexpression of TXN1 in transgenic C57BL/6 mice resulted in extended median (35%) and maximum (22%) lifespan. Telomerase activity in spleen tissues of TXN1 overexpressing mice is higher than tha in wild-type [12230882]. | Human |
| UCP2 | uncoupling protein 2 (mitochondrial, proton carrier) | Overexpression of human UCP2 in the fly nervous system extends lifespan by 10-30%. Ubiquitous overexpression is lethal [16054055]. | Human |
| APOE | apolipoprotein E | In humans APOE is located on chromosome 19. There are three common allelic variants of APOE (ε2 to ε4).
The resulting proteins are referred to as ApoE2, ApoE3 and ApoE4.
The respective proteins differ only in single amino acid, but have a dramatic influence on the life of affected humans.
The frequency of the epsilon 2 allele of ApoE is significantly increased in centenarians relative the overall control population, while the epsilon 4 allele is significantly decreased in centenarians [8136829]. Among individuals 85 years or older how had good cognition, the mortality of those that had the 2/3 genotype was half that in those who carried the epsilon 3/3 genotype and the mortality in subjects with the epsilon 3/4 genotype is twice that of those who carry the epsilon 3/3 genotype. This 4-fold variation results in 2-year difference in survival [8624216].
The epsilon 4 allele is also associated with higher cholesterol levels and cardiovascolar disease [10818513; 8624216] as well as risk factor for cognitive impariment under age 85 [8624216]. However the APOE polymorphism is not a risk factor for cognitive impairment in individuals older than 85 years [8624216].
The Polymorphism (E2, E3, and E4) was examined in a sample of 228 healthy Italian subjects (124 men and 104 women) aged 18-93, with the result that the frequency of E4 decreased with age and was not found in subjects aged 75 and older [8541369].
By Examining the common polymorphism was in 182 women and 100 men aged > 84 years and in 100 boys and 100 girls younger than 17 years (English, Cambridge) a difference between genotypes in the elderly women and the young sample was observed. However, this did not retain significance when the genotype frequencies of the young sample were adjusted to values expected from the allele frequencies on the basis of Hardy-Weinberg equilibrium and compared to observed genotypes in elderly men and women [9105559].
In a Braxiallian population the common polymorphism was examined in 70 elderly patients aged 80 years or more. No association was observed between the genotypes and longevity, though individuals with the E3E4 genotype had a mean age greater than those with the E3E3 genotype [12185856].
In a Korean population the common polymorphism examination of 103 centenarians (13 men and 90 women, mean age 102.4 +/- 2.6 years) and 6435 adults (5008 men and 1427 women) of mean age 50.7 +/- 7.9 years found that the frequencies of genotypes and alleles of the centenarians were not significantly different from those of the control groups. The frequency of the E4 allele was significantly higher in centenarians with dementia than in centenarians without definitive dementia [12634288].
Examination of the common polymorphism in 224 older (75 years) Jewish Jerusalem residents of Ashkenazi ethnicity (150 males and 74 females) and a group of 441 younger subjects (22 years) revealed that the Ashkenazi older subjects were characterized by an increased percentage of the E2 allele and a decreased percentage of the E4 allele [15621215].
A study of APOE polymorphisms in a samples of 538 Colombian subjects (aged 18-106 years) did not find any differences between young and old subjects [16971231].
APOE correlated highly with longevity in a plethora of genetic signatures and has been associated with Alzheimer's disease [22279548].
ε3 and *ε4 are much more efficient binding lipoprotein receptors [11882522].
The various APOE isoforms interact differently with specific lipoprotein receptors, ultimately altering circulating levels of cholesterol. APOE from VLDL, chylomirons and chylomicron remnants binds to specific receptor cells in the liver. Carriers of the *ε2 allele are less efficient at making and transferring VLDLs and chylomicrons from the blood plasma to the liver because of its binding properties. By contrast, carriers of the ε3 are much more efficient in these processes. While APOE4 and APOE3 bind with approximately equal affinity to lipoprotein receptors, APOE2 binds with less than 2% of this strength [7628082]. Thus, compared with carriers of the *ε3 or *ε4 allele, carriers of the *ε2 allele are slower to clear dietary fat from their blood [3479440]. The difference lipoprotein particles results in differences in regulating hepatic low density lipoprotein (LDL) receptors which in turn contribute to genotypic differences in total and LDL cholesterol levels [1998654; 3277611; 8696954; 8018666; 1867194; 3698268].
While APOE was not found to be associated with longevity in some studies [16799145; 21703254], APOE was found to be associated with longevity in many others [11780357; 11213279; 16487435; [23286790; 15621215; 8018664; 21418511; 8136829; 9792194; 22445811; 12185856; 10069711; 21703254; 17934638; 17234815; 11788960; 17934638; 10643896; 11280044; 14615589; 23040522; 18034366]. APOE was found to be associated with longevity [22445811]. APOE was not found to be associated with longevity [24924924]. APOE was found to be associated with longevity [24924924]. APOE was found to be associated with longevity [24688116]. APOE was found to be associated with longevity [24534555]. APOE was found to be associated with longevity [24244950]. APOE was found to be associated with longevity [24126160]. | Human |
| ATM | ataxia telangiectasia mutated | Individuals with ataxia-telangiectasia (AT) have a decreased lifespan, with a maximum of 52 years [3864931].ATM was found to be associated with longevity [22960875].ATM was found to be associated with longevity [20816691]. ATM was found to be associated with longevity [22960875]. ATM was found to be associated with longevity [22960875]. | Human |
| HCFC1 | host cell factor C1 (VP16-accessory protein) | HCFC1 is a cronserved protein with a predominant nuclear localisation [7876203]. The mammalian HCF-1 is involved in cell cycle progression, both at the G1/S transition and at M phase and cytokinesis [12743030 ;15200950;17612494]. It acts by binding to and regulating many different transcripts and chromatin factors and assembling appropriate protein complexes for context-dependent gene expression regulation. HCF-1 helps to recruit the activating Set1/Ash2 histone methyltransferase complex [18043729]. Mammalian HCF-1 recruits te Set1/Ash2 histone methyltransferase activating complex to E2F1 and the Sin3 histone deacetylase repressive complex to E2F4 at the appropriate time of the cell cycle, which is likely to reinforce the activating or repressive functions of the respective E2F family members [17612494]. | Human |
| MAP3K7 | mitogen-activated protein kinase kinase kinase 7 | rs282070 located in intron 1 of MAP3K7 gene was significantly associated with longevity in a Calabria (Italy) population.MAP3K7 was found to be associated with longevity [22576335]. | Human |
| GSTZ1 | glutathione transferase zeta 1 | rs21116999 located in intron 1 of the GSTZ1 gene was significantly associated with longevity in a population Calabria (Italy).GSTZ1 was found to be associated with longevity [22576335]. | Human |
| TP53 | tumor protein p53 | A naturally occuring allele with decreased p53 activity has been assoicated with extended survival [15732191].TP53 was found to be associated with longevity [23125046]. TP53 was found to be associated with longevity [18256523]. TP53 was found to be associated with longevity [15621215]. TP53 was found to be associated with longevity [18256523]. TP53 was not found to be associated with longevity [15195682]. TP53 was not found to be associated with longevity [15621215]. | Human |
| FOXO1 | forkhead box O1 | In men FOXO1A gene polymorphism (rs4943794) is possible associated with aging [22661237].FOXO1 was found to be associated with longevity [19793722]. FOXO1 was found to be associated with longevity [19793722; 19793722; 21388494]. FOXO1 was not found to be associated with longevity [18765803; 12843179]. | Human |
| FOXO3 | forkhead box O3 | FOXO3A gene polymorphism (rs3800231) may be important for achievement of longevity [22661237].FOXO3 was found to be associated with longevity [20884733]. FOXO3 was found to be associated with longevity [19793722]. FOXO3 was found to be associated with longevity [19793722]. FOXO3 was found to be associated with longevity [19793722]. FOXO3 was found to be associated with longevity [18765803]. FOXO3 was found to be associated with longevity [19196970]. FOXO3 was found to be associated with longevity [20849522]. FOXO3 was not found to be associated with longevity [20849522]. | Human |
| BLM | Bloom syndrome, RecQ helicase-like | BLM mutation cuases Bloom syndrom. Individuals with Bloom syndrome have a shortend life expectancy []. Death is primary due to cancer, particulary leukemia and lymphoma [German, 1992]. Bloom syndrome is not a premature aging disease. Bloom syndrome characteristics are grwoth deficiency, sun-snesitivity, telangiectatic hypo- and hyperpigmented skin, predisposition to malignancy, and chromosomal instability [5770175]. | Human |
| CETP | cholesteryl ester transfer protein, plasma | Homozygousity for the I405V variant of CETP is associated with exceptional longevity and larger HDL and LDL particle sizes as well as lower prevalence of hypertension, cardivascular disease, and metabolic disease among Askenazi Jews [14559957]. CETP I405V homozygousity is associated with exceptional longevity and preservation of cognitive function in Askenazi Jews [17190939].
V/V homozygotes tend to have a 9-23% CETP deficiency [9610775; 15243211]. A decrease in CETP function increases HDL (high density lipoproteins) levels in the body, and decreases LDL (low-density lipoprotein). The result of this s that HDL-c levels are approximately equal in individuals with the I/I or I/V genotypes, while there are ten percent higher in V/V individuals [9610775].
Therefore the V/V SNP acts kind like an endogenous *CEPT inhibitor*, which might be the responsible for the increase in longevity but may also have side effects.CETP was found to be associated with longevity [22336474].CETP was found to be associated with longevity [15621216].CETP was found to be associated with longevity [15888337]. CETP was found to be associated with longevity [22234866]. CETP was found to be associated with longevity [22336474]. CETP was found to be associated with longevity [23389097]. CETP was found to be associated with longevity [23389097]. CETP was found to be associated with longevity [15621216]. CETP was found to be associated with longevity [15888337]. CETP was not found to be associated with longevity [23389097]. CETP was found to be associated with longevity [14559957]. CETP was found to be associated with longevity [16602826]. CETP was found to be associated with longevity [23162014]. CETP was not found to be associated with longevity [14559957]. CETP was found to be associated with longevity [18034366]. CETP was not found to be associated with longevity [24468472]. | Human |
| ERCC8 | excision repair cross-complementing rodent repair deficiency, complementation group 8 | Individuals with a mutation in ERCC8 (alias CKN1) have a shortened lifespan, short stature, precociously senile appearance, retinal degeneration, optic atrophy, sensitivity to sunlight, and mental retardation [14156156]. Hypertension and renal disease are also common in ERCC8 mutants [514720]. | Human |
| IGF1 | insulin-like growth factor 1 (somatomedin C) | Males exhibit an age-related increase in the A-allele of rs2229765 and a change in the plasma level of IGF-1, which dropped significantly after 85 years of age. In males +over 85 years, A/A homozygous individuals have the lowest plasma IGF-1 level. However, ther was no clear correlation between rs2229765 genotype and IGF-1 in females [19460140].IGF1 was found to be associated with longevity [20199671]. IGF1 was found to be associated with longevity [18761080]. IGF1 was found to be associated with longevity [18761080]. IGF1 was found to be associated with longevity [18761080]. IGF1 was not found to be associated with longevity [19489743]. | Human |
| APBB1 | amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65) | At least one copy of the minor allele of F65 was associated with decreased risk of sporadic dementia of the Alezheimer's type as suggest by a larde epidemiological study [9799084]. Fe65 protein binds to the intracellular domain of the beta-amyloid precursor protein and may modulate the internalization of betaPP. The deletion/substitution of the minor allele occurs with the intron that interrupts the two exons encoding the betaPP binding site. Linkage of the minor allele with resistance to DAT was confirmed in another study in populations over 75 years-of-age [11065130], while epidemiological studies that did not support the linage [11436125; 11099823; 11029529] lacked representation of individuals older than 75 years-old. Any protective effect that the minor allele of Fe65 might have is probably restricted to individuals older than 75 years. | Human |
| GH1 | growth hormone 1 | Mean lifespan in untreated, affected individuals homozyogus for a deletion at the GH1 locus is significantly shorter (P < 0.05) than in affected siblings or the general population. Individuals homozygous for GH1 deletion demonstrate hereditary dwarfism [12915652]. GH1 was found to be associated with longevity [15771611]. | Human |
| HSPA9 | heat shock 70kDa protein 9 (mortalin) | Overexpression of HSPA9 (mortalin) increases the proliferation potential of normal fibroblasts [11959102]. Transfection of normal human fibroblasts with human HSPA9 (or the murine Hspa9) overexpression vectors led to an increase in the number of population doublings the cells could sustain before senescing (increase varying from 32-60%, depending on the exact construct used). Transfected cells retain a youthful morphology longer than the controls cells, and there is an dealy in appearance of senescence associated beta-galactosidase activity [10838077]. Mot-2 overexpressing cells exhibit a reduction in p53 transcriptional activation (as measured by expression from vectors containing either luciferase or beta-glactosidase driven by p53 binding sites) [10838077], which might partially or wholly explain the effects of Mot-2 on proliferative potential. HSPA9 is differentially distributed and/or translated in normal vs. transformed cells [8454632]. | Human |
| TERT | telomerase reverse transcriptase | Telomerase-expressing cells (human foreskin fibroblasts, retinal pigment epithelial cells) maintain normal length of telomeres and continue to divide vigorously [9454332]. Cells expression telomerase have reduced staining for beta-galactosidase (a biomarker of cellular senescence) [9501072]. TERT expression is also able to prevent the accelerated replicative senescence observed in cells taken from Werner's patients [10615119].
A haplotype of TERT was correlated with both longer both longer telomere length and exceptional longevity. Mutations in TERT were overpresented in Ashkenazi centenarians [19915151].TERT was not found to be associated with longevity [22136229]. TERT was found to be associated with longevity [23562826]. | Human |
| SOD1 | superoxide dismutase 1, soluble | Ubiquitous overexpression of SOD1 does not extend lifespan in mice. Homozyous transgenic mice with two- to five-fold overexpression of SOD1 in various tissues exhibit a light reduction in lifespan. Hemizygous transgenic mice, with 1.5- to 3-fold overexpression of SOD1 display no difference in lifespan compared with nontransgenic litermate controls [10719757]. Transgenic mice with a mutant SOD1 transgene develop neuronal cytoskeletal lesions resembling the human amytrophic lateral sclerosis (ALS) phenotype [8610185]. Transgenic mice overexpressing SOD1 (and having 3.1-fold higher cellular Cu,Zn SOD activity in the brain) have reduced infarct size following experimental cerebral ischemia [1763030].SOD1 was not found to be associated with longevity [24163049]. | Human |
| MAPT | microtubule-associated protein tau | Expression of wild-type human MAPT (tau) moderately shortened lifespan. Expression of a mutant form of human MAPT (Arg406 Trp), associated with an early onset familial form of demetia, results in a several shortened lifespan. MAPT is implicated in the pathogenesis of Alzeimer's disease and related disorders in humans. Transgenic flies exhibit key features of the human disorders: adult onset, progressive neurodegeneration, early death, enhanced toxicity of mutant tau, accumulation of abnormal tau, and relative anatomic selectivity. However, neurodegeneration occurred without the neurofibrillary formation that is observed in humans disease and some rodent taupathy models [11408621]. | Human |
| LMNA | lamin A/C | Dominant mutation in LMNA (lamin A/C) gene cause Hutchinson-Gilford progeria syndrome (HGPS) which is rare and characterized by prematurly senile appearing skin and hair, with death from coronary artery disease often by age 10 [Gilford 1904; Hutchinson 1886; OMIM]. The median age of death in HGPS individuals is 13.4 years. A C to T transition at nucleotide 1824 is associated with HGPS [Sandra-Giovannoli et al., 2003; Eriksson et al., 2003]. The 1824C-T allele appears to act in a dominant negative manner by interfering with normal splicing, resulting in production of both the normal transcript and a transcript deleted for 150 bp at the 3' end [Sandre-Giovannoli et al, 2003]. Cultured skin fibroblasts from individuals with progeria exhibit an increased fraction of hat-labile proteins [1128606].
Gilford (1904). Ateleiosis and progeria: continuous youth and premature old age. Brit Med J 2, 914-918.
Hutchinson, J. (1886). Case of congenital absence of hair, with atrophic condition of the skin and its appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six. Lancet 1, 923.LMNA was found to be associated with longevity [22340368]. LMNA was found to be associated with longevity [22340368]. LMNA was found to be associated with longevity [22279548]. LMNA was found to be associated with longevity [24244950]. | Human |
| 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 |
| KL | klotho | The KL-VS allele of the klotho gene is more common in infants than in elderly individuals. Individuals homozygous for KL-VS have a 2.6-fold greater chance of dying by age 65 than individuals that are homozyogous that are homozyogous for the wild-type klotho allele [11792841]. KL was found to be associated with longevity [17903295; 22406557; 15677572]. KL was not found to be associated with longevity [18034366]. KL was found to be associated with longevity [24164579]. | Human |
