seq2func

Sequence-to-Function Longevity Gene Knowledge Base

Longevity-Associated Genes

22 genes

APOE

apolipoprotein E

APOE is involved in lipid metabolism. Mice without APOE show dysregulations in lipid metabolism, having higher plasma cholesterol levels and developing arterial lesions, displaying DNA oxidative stress at a hepatic level, and presenting severe atherosclerosis and cutaneous xanthomatosis. They also have a significantly shorter lifespan than wild-type. Neurodegeneration has also been reported in APOE-null mice. Several polymorphisms in the human APOE gene have been associated with diseases, such as increased risk of myocardial infarction and Alzheimer’s disease. Polymorphisms in APOE have been linked to human longevity. There are four isoforms of APOE in humans. In Alzheimer’s disease the ApoE2 isoform is protective and the ApoE4 isoform is causative and stimulates amyloid beta production. ApoE4 also exacerbates tauopathy in mouse models of Alzheimer’s disease and ApoE4 knock-in mice show significantly higher levels of tau in the brain. Despite its association with age-related disease the ApoE4 isoform is the second most common after the ApoE3 isoform and is the ancestral form of APOE. Clearly, APOE has an impact on various age-related diseases, such as atherosclerosis and neurodegeneration, but its overall impact on the human ageing process remains to be determined.

ATM

ATM serine/threonine kinase

ATM is involved diverse aspects of cellular physiology including DNA repair and cell cycle control. It appears to activate DNA repair pathways in response to DNA damage. Mutations in human ATM cause ataxia telangiectasia, an early-onset disease some argue is characterized by signs of premature ageing. Patients display cerebellar atrophy and neurodegeneration. In mouse and worm models that are ATM deficient replenishing intracellular NAD+ reduces the severity of neuropathy, normalizes neuromuscular function, delays memory loss, and extends lifespan. In mice, mutations in ATM in late-generation TERC mutants with short telomeres results in signs of premature ageing starting at about 6 months of age. In mouse and human cells ATM is required for the recruitment of telomerase and inhibition of ATM leads to shortening of telomeres. However, it has also been shown that inhibiting ATM attenuates senescence. Inhibiting ATM induces the functional recovery of the lysosome/autophagy system and accelerates the removal of dysfunctional mitochondria. Overall, it is possible ATM plays a role in human ageing and may link two major theories on ageing: DNA damage accumulation and mitochondrial dysfunction.

BRCA1

breast cancer 1, early onset

BRCA1 is crucial in cellular responses to DNA damage and may also be a transcriptional regulator. It interacts with WRN. Mutations in BRCA1 result in embryonic lethality in mice and humans. Mice hypomorphic for BRCA1 and heterozygous for TP53 have slower growth rates and display signs of premature ageing starting at about 8 months of age. Loss or haploid loss of CHEK2 also enables mice lacking BRCA1 to avoid embryonic lethality and display signs of premature ageing at about 18 months of age and develop multiple tumours later in life. In humans, some evidence suggests differences in BRCA1 genotype frequencies between centenarians and controls. BRCA1's role in cancer in humans is undisputed, and it is possible it also plays a role in ageing.

CAT

catalase

Catalase is an antioxidant that protects cells from hydrogen peroxide. Some experiments in invertebrates suggest a role for CAT in ageing. Overexpression of CAT and SOD1 in short-lived strains of fruit flies extends lifespan and appears to delay ageing, but the same effects are not witnessed in long-lived strains. CAT overexpression targeted to mitochondria extends longevity in mice, but this appears to be related to a lower incidence of cardiac pathology rather than delayed ageing. These mutants are also more resistant to age-related skeletal muscle dysfunction and exhibit improved voluntary exercise, increased muscle force, decreased intracellular Ca(2+) leak and increased sarcoplasmic reticulum Ca(2+) load. Cardiac-specific overexpression prolongs lifespan in mice. Although it has been argued that CAT plays a role in ageing, there is no direct evidence linking CAT to human ageing.

CDKN2A

cyclin-dependent kinase inhibitor 2A

The CDKN2A gene encodes different transcripts involved mostly in cell cycle regulation and cellular senescence, including the tumour suppressor proteins p16 and p19. At least three alternatively spliced variants encoding distinct proteins have been reported. CDKN2A expression levels increase with age in rodents. In one study, increased CDKN2A dosage in mice resulted in cancer resistance and normal ageing. Conditional expression of transgenic p16 in mice strongly inhibits proliferation of normal and stem- intestinal cells, cell cycle progression, and causes several signs of premature ageing (reduced hair density and diameter, variable lightening of hair colour, lower weight, and kyphosis, etc.). These features of premature ageing are reversible through de-induction of p16. p16 induced senescence in mouse pancreatic beta cells enhances INS secretion. One study in progeroid mice reported that the clearance of senescent cells expressing CDKN2A delays ageing-associated phenotypes, such as lordokyphosis, sarcopenia and cataracts, although it does not extend lifespan. In normal mice, the clearance of p16 positive cells delays tumorigenesis, increases lifespan and attenuates age-related deterioration of several organs without apparent side effects. In contrast, increased but regulated CDKN2A and TP53 activity has been found to ameliorate age-associated central nervous system functional decline in mice, acting to maintain the neural stem cell pool. Regulated CDKN2A activity provides a mechanism for extended lifespan and health span in mice. Loss of CDKN2A in mice has been reported to result in tumour susceptibility. Mice deficient in CDKN2A also showed a smaller age-related decline in self-renewal potential as this process is associated with increasing levels of CDKN2A. In geriatric mice, satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, due to derepression of CDKN2A. Silencing of CDKN2A restores the cell quiescence. Mutations in the human CDKN2A gene have been associated with cancer. Therefore, although it is clear CDKN2A is involved in cancer and is a marker of ageing, its mechanistic role in human ageing remains unknown.

FOXO1

forkhead box O1

A transcription factor of the Fox family, FOXO1 is important in development. It also appears to regulate apoptotic signals.A homologue of FOXO1A, daf-16, has been associated with ageing in roundworms, and overexpression of another homologue, dFOXO, in adult fat body of fruit flies increased longevity in females. Mice overexpressing FOXO1 in skeletal muscle weighed less than controls and had a reduced skeletal muscle mass, suggesting that FOXO1 could play a role in the age-related decline in muscle mass. Results from mice also suggest that FOXO1 could be involved in type 2 diabetes. Although at present there is no evidence directly linking FOXO1 to human ageing, it remains a putative player in the human ageing process.

FOXO3

forkhead box O3

A transcription factor of the Fox family, FOXO3, is crucial in development. It also appears to regulate apoptotic signals in conjunction with FAS and AKT1. A homologue of FOXO3, daf-16, has been associated with ageing in roundworms, and overexpression of another homologue, dFOXO, in adult fat body of fruit flies increased longevity in females. Female mice without FOXO3 showed an ovarian phenotype of follicular activation leading to oocyte death, early depletion of functional ovarian follicles, and secondary infertility. Two studies of genetic variation within FOXO3, have found it to be associated with exceptional human longevity, among people of Japanese and German origin. The G allele of FOXO3 single nucleotide polymorphism (SNP) rs2802292 has been associated with longevity in multiple populations. G-allele carriers among combined Japanese, white and black populations have a risk reduction of 10% for total mortality.

HIF1A

hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)

HIF1A is a transcription factor that responds to oxidative stress and oxygen. Changes in HIF1A with age have been reported in rats and could be related to age-related pathologies, such as neurodegeneration. Deficiencies in HIF1A have not been associated with ageing in mice. Further evidence is needed to directly link HIF1A to human ageing.

IGF1R

insulin-like growth factor 1 receptor

The receptor for IGF1, IGF1R, mediates the activation of the IGF1-stimulated signalling cascade. Evidence from model organisms, including results from flies and roundworms, relates IGF1R homologues to ageing, most likely as part of the GH1/IGF1 axis. Mice (129/SvPas genetic background) heterozygous for IGF1R live 26% longer, though it is unclear whether they age slower. Null mutants are not viable. In the B6 genetic background however, IGF-1R+/- female mutants show only an 11% lifespan extension, while males do not show any changes in median lifespan and have a slightly shorter maximum lifespan. In male mice where IGF1R has been knocked out specifically in cardiomyocytes, cardiac ageing is attenuated. Fibrosis and expression of proinflammatory cytokines and NFKB1 are reduced when compared to wild type mice. IGF1R integrates nutrient and temperature homeostasis in mice and a reduction in IGF1R enhances the reduction of temperature and energy expenditure seen during calorie restriction. Therefore, IGF1 signalling plays a role in regulating hypothermia during calorie restriction. The IGF1/GH1 axis appears to impact on ageing in model organisms, including rodents, and so IGF1R may affect human ageing. In humans, IGF1R has been implicated with growth retardation, and genotype combinations in the human IGF1R and PIK3CB genes have been related to plasma IGF1 levels and longevity.

KL

klotho

The KL gene encodes two proteins: one membrane protein and one secreted transcript that acts as a circulating hormone. KL regulates INS, Wnt, and FGF23 signalling. Mice mutant for KL show multiple signs of accelerated ageing. The accelerated ageing phenotype of KL deficient mice is similar to that observed in FGF23 deficient mice. KL binds FGF receptors and is a co-factor essential for the activation of the receptor. In this process KL acts as a scaffold protein and tethers the FGF receptor to FGF23 by its C-terminal tail, conferring stability to the complex. In contrast, overexpression of KL in mice increases lifespan by 20-30% (perhaps through repression of intracellular INS/IGF1 signals), dramatically improves renal function, and protects against neurodegenerative diseases such as Alzheimer’s and Parkinson’s. KL enhances neuroprotection and normal cognition, in part, by optimising synaptic functions. Peripheral expression of a KL fragment enhanced brain function in young and ageing mice, in addition to an alpha-synuclein transgenic mouse model of Parkinson’s disease. The KL fragment induced cleavage of an NMDAR subunit and increased synaptic plasticity. Injection of KL into the central nervous system resulted in enhanced learning and memory 6 months after injection. KL alleles have also been implicated in human longevity and age-related diseases. Even though its other functions remain a mystery, KL may also be involved in calcium metabolism and in a vitamin D endocrine system. Premature ageing phenotypes in mice mutant for KL are largely rescued by keeping the animals on a vitamin-D-deficient diet. It is plausible that KL plays some role in human ageing but more work is necessary to confirm this notion and elucidate the mechanisms involved.

LMNA

lamin A/C

LMNA encodes both lamin A and C (lamin A/C), two components of the lamina, a layer of the inner nuclear membrane that may interact with chromatin. Hutchinson-Gilford's progeroid syndrome, caused by a mutation in LMNA, is characterized by features resembling accelerated ageing. Cells from Hutchinson-Gilford's progeroid syndrome patients are characterised by accumulation of abnormally shaped nuclei, accumulation of DNA damage and premature senescence. LMNA mutations (such as the G608G mutation) generate more accessible splicing donor sites and lead to the production of an alternatively spliced product of LMNA called progerin, normally found in ageing cells. Progerin binds directly to lamin A/C and induces profound nuclear aberrations in human cells. Mice Lmna mutants containing the G690G mutation, which also display an increased ratio of progerin/Lamin A, have shorter lifespan compared to the wild-type ( ~40% in heterozygous mice, and ~83% in homozygous mice), while mice with Lmna LCS, a knock-in mutation responsible for specifically not-producing progerin, display an increased lifespan (~13% in heterozygous mice and ~10% in homozygous mice). Lamin A/C are TP53BP1 binding proteins that promote TP53BP1 nuclear retention. Lmna knockout mouse embryonic fibroblasts are deficient in TP53BP1 and are unable to carry out the NHEJ DNA repair pathway. Sustained expression of progerin in mouse adipocytes results in senescence, DNA damage, inflammation, fibrosis and lipoatrophy. The findings suggested that adipose tissue is particularly sensitive to progerin expression. In flies LamC mutations are a model of human LMNA mutations. The flies demonstrate premature ageing in adult flight muscles and have decreased levels of specific mitochondrial protein transcripts and progressive mitochondrial degradation. Several transcripts required for mitochondrial integrity and function exit the nucleus via nuclear envelop budding. Abnormal lamina organisation due to LamC mutation may prevent the egress of these RNAs. Thus, absence of LMNA may accelerate ageing due to an impaired response to DNA damage and mitochondrial dysfunction. Overall, LMNA is one of the most promising candidates for a gene related to human ageing.

MTOR

mechanistic target of rapamycin (serine/threonine kinase)

The MTOR kinase belongs to the target of rapamycin group of enzymes which regulate cellular growth and proliferation. TOR enzymes, homologues of MTOR, have been linked to ageing in lower organisms. In yeast, deletions in the nutrient-responsive TOR pathway increased lifespan, and caloric restriction failed to further increase lifespan. Similarly, in roundworms, TOR deficiency more than doubled the lifespan, and TOR disruption in fruit flies also extended lifespan. In invertebrates, a functional link between MTOR and insulin (INS)/IGF1 signalling has been proposed, which further hints of a role for MTOR in ageing. Mice hypomorphic for mTOR have reduced mTORC1 expression, are smaller and live 20% longer. Female mice heterozygous for both mTOR and mLST8 also exhibit decreased mTORC1 activity and extended life span but have normal glucose tolerance and insulin sensitivity. While rapamycin also disrupts the mTORC2 complex, the lifespan extension is mediated through the mTORC1 complex. MTORC1 activity is reduced in the tissues of three long lived mice mutants: Snell dwarf mice (POU1F1 mutants), GHR knockout mice and PAPPA knock-out mice. In GHR knockout mice mTORC2 signalling is upregulated. Treating GHR knockout mice with rapamycin causes no further downregulation of mTORC1 but does interfere with mTORC2 and disrupts whole body homoeostasis. There, mTORC1 and mTORC2 play different roles in the ageing process. In human cell cultures MTOR inhibition supresses the senescence associated secretory phenotype (SASP), which can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR normally acts to regulate the SASP by promoting IL1A translation, which in turn promotes NFKB1 transcriptional activity. More work is needed to determine whether MTOR is associated with human ageing but it is a promising target for further research.

MYC

v-myc avian myelocytomatosis viral oncogene homolog

MYC regulates gene transcription and appears to promote growth. It is also an oncogene, involved in cellular senescence. Overexpression of Myc in flies increases the frequency of somatic mutations, and shortens median and maximum lifespan by up to 47%. Contrastly, Myc haploinsufficiency lowers the frequency of somatic mutations and extends the lifespan of flies by about 14%. Among its many interacting partners, MYC has been linked to ageing-related genes such as WRN and TERT, and hence might play some, so far unknown, role in human ageing.

NFE2L2

nuclear factor, erythroid 2-like 2

Also known as NFE2L2, NF-E2-related factor 2 (NRF2) is a transcription factor that is activated by oxidative stress and electrophiles and has a role in inducing a number of antioxidative and carcinogen-detoxifying enzymes. Nrf2-deficient mice develop more tumors in response to carcinogens, and caloric restriction is ineffective in suppressing them in knockout mice. In contrast, caloric restriction remains effective in extending lifespan and increasing insulin sensitivity. In Nrf2-null mice fed a high-fat diet, the levels of hepatic triglycerides and cholesterol in liver were similar to wild type, while the levels of hepatic free fatty acid and malondialdehyde equivalents were higher, suggesting that Nrf2 inhibits lipid accumulation and oxidative stress in the mouse liver. In human fibroblasts, NRF2 shows a declined function in replicative senescence and its silencing leads to premature senescence. NRF2 activation results in the enhanced survival of cells following oxidative stress, whereas continuous treatment leads to lifespan extension of human fibroblasts. NRF2 has been also linked to several human age-related diseases, including atherosclerosis, neurodegenerative diseases, and cancer. It has been shown that progerin, an alternatively spliced product of LMNA involved in Hutchinson-Gilford progeria syndrome, sequesters NRF2, resulting in impaired NRF2 activity and increased oxidative stress. Suppressed NRF2 activity or increased oxidative stress is sufficient to recapitulate some of the accelerated aging effects seen in Hutchinson-Gilford progeria syndrome patients. Thus, NRF2 may play a role in accelerated human aging.

PPARGC1A

peroxisome proliferator-activated receptor gamma, coactivator 1 alpha

PPARGC1A is a transcriptional coactivator that regulates and interacts with genes involved in energy metabolism. It has a role in regulating metabolism, inflammation, oxidative stress resistance and mitochondrial biogenesis and function. SIRT1 has been reported to be a functional regulator of PPARGC1A. In mice, knockout of PPARGC1A accelerates vascular aging and atherosclerosis, coinciding with telomere dysfunction and shortening and DNA damage. Expression of PPARGC1A coactivates TERT transcription and reverses telomere malfunction. In humans, PPARGC1A has been associated with cholesterol and obesity as well as age-related diseases like type 2 diabetes. Thus, PPARGC1A may play a role in in ameliorating senescence, aging, and age-associated chronic diseases.

SIRT1

sirtuin 1

SIRT1 is a NAD-dependent deacetylase, which can regulate a number of processes by deacetylating key proteins, such as TP53. In yeast, the SIRT1 homologue sir2 has been linked to cellular senescence. Increasing the levels of SIRT1 homologues in fruit flies and roundworms extends lifespan, although these findings have been questioned by other studies. SIRT1-null mice are born smaller than controls with evidence of developmental retardation. Depending on their genetic background, SIRT1-null mice either die shortly after birth or reach adulthood, the latter being smaller than controls and sterile. Additionally, SIRT1-null mice utilize ingested food inefficiently, are hypermetabolic, contain inefficient liver mitochondria, have elevated rates of lipid oxidation and do not display an extended lifespan under caloric restriction. Heterozygous mice had a normal average lifespan. Mice with moderate overexpression of SIRT1 exhibit fat mass gain similar to controls exposed to a high-fat diet. Cardiac-specific low to moderate overexpression of SIRT1 attenuated age-dependent increases in cardiac hypertrophy, apoptosis, and expression of senescent biomarkers while a high level of overexpression had detrimental effects and induced cardiomyopathy. Overall, whole-body moderate overexpression of Sirt1 improves healthy ageing but does not increase mice lifespan. Brain-specific overexpression in mice results in moderately longer lifespan as females live 16% longer and males 9% longer. SIRT1 is overexpressed in calorie restricted rats, a response attenuated by insulin (INS) and IGF1. Increased dosage of SIRT1 in pancreatic beta cells enhanced INS secretion. In Cockayne syndrome, an accelerated ageing disease, activation of SIRT1 through a high-fat diet and NAD(+) supplementation results in the rescue the mice from the associated progeroid phenotypes. In murine induced pluripotent stem cells, SIRT1 is necessary for telomere elongation after reprogramming and is required to maintain genomic stability, telomeric transcription and remodeling of telomeric chromatin. SIRT1-deficient induced pluripotent stem cells accumulate chromosomal aberrations and show a derepression of telomeric heterochromatin. In humans, increased levels of SIRT1 and SIRT3 have been associated with frailty. Although SIRT1 could impact on age-related diseases, such as type 2 diabetes, further studies are needed to establish its role in human ageing.

SIRT6

sirtuin 6

In yeast, sirtuins regulate epigenetic gene silencing. SIRT6, a chromatin-associated protein, also appears to be involved in DNA repair. SIRT6-null mice are small, with low levels of IGF1, display evidence of genomic instability, and exhibit signs of premature ageing after 2-3 weeks. One of the roles of SIRT6 appears to be repression of L1 retrotransposons' activity, thus contributing to genome stability. This characteristic however declines over the course of ageing and in response to DNA damage. Overexpression of SIRT6 increases lifespan by 10-14.5% in mice males, but not in females. SIRT6 intraarticular injection is protective against chondrocyte degeneration. In mice overexpressing exogenous SIRT6 (MOSES mice) both lifespan and health span are increased. MOSES mice show improved glucose tolerance, younger hormonal profile, reduced age-related adipose inflammation and increased physical activity. MOSES mice fed on a high fat diet accumulate less fat and show improved glucose tolerance. These mice also show reduced levels of circulating IGF1. In humans SIRT6 levels were reduced in the articular chondrocytes of osteoarthritis patients. In chondrocyte cell cultures SIRT6 overexpression supresses replicative senescence, thus inhibiting the inflammatory senescence associated secretory phenotype (SASP). The expression of NFKB1 dependent genes is significantly attenuated by SIRT6 overexpression. As such, it is possible that SIRT6 plays a role in human ageing and could ameliorate age-related pathologies.

SOD2

superoxide dismutase 2, mitochondrial

SOD2 is an antioxidant, the mitochondrial form of SOD and an important defence against oxidative damage. Evidence from invertebrates suggests it may play a role in ageing. Overexpression of SOD2 in flies significantly extends lifespan. Mice without SOD2 are not viable. Reducing the activity of SOD2 in mice increases the levels of oxidative damage to DNA but does not affect lifespan. SOD2 overexpression in mice slightly increases lifespan, while gene deletion in connective tissue only resulted in mutant mice with a reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis, osteoporosis and muscle degeneration. Loss of SOD2 activity in the epidermis induces cellular senescence. In the long-lived alphaMUPA mice strain, a reduced level of SOD2 gene expression and activity is observed together with maintaining the capacity to produce high levels of SOD2 in response to the inflammatory stimulus. Exercise training elevates levels of SOD2 in aging mouse hearts. Overexpression of SOD2 in aging mouse hearts demonstrated a protective role against oxidative stress, fibrosis and apoptosis. Surprisingly, young mice with epidermal SOD2 deficiency have accelerated wound closure. In contrast, old mice with epidermal SOD2 deficiency show delayed wound closure, reduced epidermal thickness and epidermal stem cell exhaustion. Polymorphisms in the human SOD2 gene have been associated with type 2 diabetes and cardiomyopathy. A longevity-associated polymorphism was observed for Ashkenazi males, but not for Italian and Jordanian populations. Although it is possible that SOD2 plays a role in human ageing, further studies are needed to investigate this hypothesis.

TERC

telomerase RNA component

The RNA component of telomerase, TERC is involved in elongating the telomeres and is a critical factor in cellular senescence.TERC disruption in mice shortens lifespan and increases tumour incidence but it does not appear to accelerate ageing. Late-generation mice with disrupted TERC, and hence with shorter telomeres, when combined with mutations in ATM or WRN may suffer from accelerated ageing. Telomere shortening in mice lacking TERC also appears to impact on the pathologies caused by mutations in BLM. Human mutations in TERC are a cause of dyskeratosis congenita, a skin and bone marrow failure syndrome which is not classified as accelerated ageing.

TERT

telomerase reverse transcriptase

Telomerase repairs/elongates the telomeres and is crucial in cellular proliferation. TERT expression is sufficient to overcome cellular senescence in culture, but overexpression of TERT in mice does not extend longevity. Most human cell lines have low or insignificant levels of TERT while cancer cells often have high levels. TERT expression in primary human fibroblasts results in a linear increase in DNA methylation age with cell population doubling number, indicating that TERT may also play a role in regulating the epigenetic clock. Cardiac-specific Tert activation after myocardial infarction in adult mice results in attenuated cardiac dilation, improved ventricular function, smaller infarct scars and increased mouse survival. Tert expression in a mouse model of pulmonary fibrosis improved lung function and lowered inflammation and fibrosis in addition to lowering DNA damage, apoptosis and senescence. In humans, mutations in TERT have been linked to aplastic anaemia. As such, TERT appears to be an important player in cellular proliferation, even if its relation to human ageing remains obscure.

TP53

tumor protein p53

TP53 is a tumour suppressor involved in cell cycle regulation, apoptosis, and DNA repair. Several lines of evidence from model organisms link TP53 to ageing, in agreement with its DNA damage protection role. In flies, expression of a dominant-negative version of TP53 extends lifespan. Mice with a permanently activated form of TP53 display signs of premature ageing starting at about 18 months of age, as do mice heterozygous for TP53 that lack BRCA1. Overexpression of p44 (one of the short isoforms of p53) also causes a progeroid phenotype, including phosphorylation of tau, synaptic deficits, and cognitive decline. Additionally, levels of p44 increase with age in the mouse brain. However, increased but regulated TP53 and CDKN2A activity has been found to ameliorate age-associated central nervous system functional decline in mice, acting to maintain the stem cell pool. This regulated TP53 activity provides a mechanism for extended lifespan and also health span in mice. Human mutations in TP53 have been associated with cancer. People with a polymorphism that decreases the apoptotic potential of TP53 have increased survival despite a higher proportional mortality from cancer. The myriad of functions and interactions of TP53, as well as the findings from model organisms, make it a possible player in human ageing.

WRN

Werner syndrome, RecQ helicase-like

Werner syndrome (WS), caused by mutations in WRN, is probably the most dramatic segmental progeroid syndrome. Although there are differences between the pathobiology of normal ageing and the phenotype of WS, the age-related changes of WS patients are remarkably similar to those found during normal ageing, only they occur at earlier ages. WRN is one of the strongest candidates for genes influencing human ageing. WRN-deficient mice display reduced embryonic survival, increased tumour formation, and their fibroblasts show features similar to those found in fibroblasts derived from WS patients such as a premature loss of proliferative capacity, though their ageing process appears unaltered. In late-generation mice without TERC, and hence with short telomeres, WRN mutations result in a phenotype resembling accelerated ageing somewhat reminiscent from WS. WRN is a helicase and exonuclease involved in many DNA repair and processing pathways. Genetic variation studies in breast cancer patients, showed that WRN might have an important tumorigenic role. Human WRN-null mesenchymal stem cells show several features associated with accelerated aging. These include increased senescence associated markers, activation of the senescence-associated secretory phenotype and an increased DNA damage response. In addition, there is a global loss of H3K9me3 and accompanying changes in heterochromatin architecture. It was shown that WRN associates with heterochromatin proteins SUV39H1 and HP1a and nuclear lamina-heterochromatin anchoring protein LAP2b. Thus, WRN may play a role in maintaining heterochromatin stability as part of its role in the ageing process.