progeroid syndromes progeroid syndromes progeroid syndromes (ps) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. the term progeroid syndrome does not necessarily imply progeria (hutchinson–gilford progeria syndrome), which is a specific type of progeroid syndrome. progeroid means "resembling premature aging," a definition that can apply to a broad range of diseases. familial alzheimer's disease and familial parkinson's disease are two well-known accelerated-aging diseases that are more frequent in older individuals. they affect only one tissue and can be classified as unimodal progeroid syndromes. segmental progeria, which is more frequently associated with the term progeroid syndrome, tends to affect multiple or all tissues while causing affected individuals to exhibit only some of the features associated with aging. all disorders within this group are thought to be monogenic, meaning they arise from mutations of a single gene. most known ps are due to genetic mutations that lead to either defects in the dna repair mechanism or defects in lamin a/c. examples of ps include werner syndrome (ws), bloom syndrome (bs), rothmund–thomson syndrome (rts), cockayne syndrome (cs), xeroderma pigmentosum (xp), trichothiodystrophy (ttd), combined xeroderma pigmentosum-cockayne syndrome (xp-cs), restrictive dermopathy (rd), and hutchinson–gilford progeria syndrome (hgps). individuals with these disorders tend to have a reduced lifespan. progeroid syndromes have been widely studied in the fields of aging, regeneration, stem cells, and cancer. the most widely studied of the progeroid syndromes are werner syndrome and hutchinson–gilford progeria, as they are seen to most resemble natural aging. defects in dna repair one of the main causes of progeroid syndromes is genetic mutations, which lead to defects in the cellular processes which repair dna. the dna damage theory of aging proposes that aging is a consequence of the accumulation of naturally occurring dna damages. the accumulated damage may arise from reactive oxygen species (ros), chemical reactions (e.g. with intercalating agents), radiation, depurination, and deamination. mutations in three classes of dna repair proteins, recq protein-like helicases (recqls), nucleotide excision repair (ner) proteins, and nuclear envelope proteins lmna (lamins) have been associated with the following progeroid syndromes: werner syndrome (ws) bloom syndrome (bs) rothmund–thomson syndrome (rts) cockayne syndrome (cs) xeroderma pigmentosum (xp) trichothiodystrophy (ttd) recq-associated ps recq is a family of conserved atp-dependent helicases required for repairing dna and preventing deleterious recombination and genomic instability. dna helicases are enzymes that bind to double-stranded dna and temporarily separate them. this unwinding is required in replication of the genome during mitosis, but in the context of ps, it is a required step in repairing damaged dna. thus, dna helicases, such as recq, maintain the integrity of a cell, and defects in these helicases are linked to an increased predisposition to cancer and aging phenotypes. thus, individuals with recq-associated ps show an increased risk of developing cancer, which is caused by genomic instability and increased rates of mutation. there are five genes encoding recq in humans (recq1-5), and defects in recql2/wrn, recql3/blm and recql4 lead to werner syndrome (ws), bloom syndrome (bs), and rothmund–thomson syndrome (rts), respectively. on the cellular level, cells of affected individuals exhibit chromosomal abnormalities, genomic instability, and sensitivity to mutagens. werner syndrome werner syndrome is inherited in an autosomal recessive manner, which means both parents must contribute a dysfunctional allele for an individual to develop the disease. main article: werner syndrome werner syndrome (ws) is a rare autosomal recessive disorder. it has a global incidence rate of less than 1 in 100,000 live births, although incidences in japan and sardinia are higher, where it affects 1 in 20,000-40,000 and 1 in 50,000, respectively. as of 2006, there were approximately 1,300 reported cases of ws worldwide. affected individuals typically grow and develop normally until puberty, when they do not experience the typical adolescent growth spurt. the mean age of diagnosis is twenty-four. the median and mean age of death are 47-48 and 54 years, respectively; the main cause of death is cardiovascular disease or cancer. affected individuals can exhibit growth retardation, short stature, premature graying of hair, hair loss, wrinkling, prematurely aged faces, beaked noses, skin atrophy (wasting away) with scleroderma-like lesions, loss of fat tissues, abnormal fat deposition leading to thin legs and arms, and severe ulcerations around the achilles tendon and malleoli. other signs include change in voice, making it weak, hoarse, or high-pitched; atrophy of gonads, leading to reduced fertility; bilateral cataracts (clouding of lens); premature arteriosclerosis (thickening and loss of elasticity of arteries); calcinosis (calcium deposits in blood vessels); atherosclerosis (blockage of blood vessels); type 2 diabetes; loss of bone mass; telangiectasia; and malignancies. in fact, the prevalence of rare cancers, such as meningiomas, are increased in individuals with werner syndrome. approximately 90% of individuals with werner syndrome have any of a range of mutations in the eponymous gene, wrn, the only gene currently connected to werner syndrome. wrn encodes the wrnp protein, a 1432 amino acid protein with a central domain resembling members of the recq helicases. wrnp is active in unwinding dna, a step necessary in dna repair and dna replication. since wrnp's function depends on dna, it is only functional when localized to the nucleus. mutations that cause werner syndrome only occur at the regions of the gene that encode for protein and not at non-coding regions. these mutations can have a range of effects. they may decrease the stability of the transcribed messenger rna (mrna), which increases the rate at which they are degraded. with fewer mrna, fewer are available to be translated into the wrnp protein. mutations may also lead to the truncation (shortening) of the wrnp protein, leading to the loss of its nuclear localization signal sequence, which would normally transport it to the nucleus where it can interact with the dna. this leads to a reduction in dna repair. furthermore, mutated proteins are more likely to be degraded than normal wrnp. apart from causing defects in dna repair, its aberrant association with p53 down-regulates the function of p53, leading to a reduction in p53-dependent apoptosis and increase the survival of these dysfunctional cells. cells of affected individuals have reduced lifespan in culture, more chromosome breaks and translocations and extensive deletions. these dna damages, chromosome aberrations and mutations may in turn cause more recq-independent aging phenotypes. bloom syndrome main article: bloom syndrome bloom syndrome (bs) is a very rare autosomal recessive disorder. incidence rates are unknown, although it is known to be higher in people of ashkenazi jewish background, presenting in around 1 in 50,000. approximately one-third of individuals who have bs are of ashkenazi jewish descent. there is no evidence from the bloom's syndrome registry or from the peer-reviewed medical literature that bs is a progeroid condition associated with advanced aging. it is, however, associated with early-onset cancer and adult-type diabetes and also with werner syndrome, which is a progeroid syndrome, through mutation in the recq helicases. these associations have led to the speculation that bs could be associated with aging. unfortunately, the average lifespan of persons with bloom syndrome is 27 years; consequently, there is insufficient information to completely rule out the possibility that bs is associated with some features of aging. people with bs start their life with a low weight and length when they are born. even as adults, they typically remain under 5 feet tall. individuals with bs are characterized by low weight and height and abnormal facial features, particularly a long, narrow face with a small lower jaw, a large nose and prominent ears. most also develop photosensitivity, which causes the blood vessels to be dilated and leads to reddening of the skin, usually presented as a "butterfly-shaped patch of reddened skin across the nose and cheeks". other characteristics of bs include learning disabilities, an increased risk of diabetes, gastroesophageal reflux (ger), and chronic obstructive pulmonary disease (copd). ger may also lead to recurrent infections of the upper respiratory tract, ears, and lungs during infancy. bs causes infertility in males and reduced fertility and early-onset menopause in females. in line with any recq-associated ps, people with bs have an increased risk of developing cancer, often more than one type. bs is caused by mutations in the blm gene, which encodes for the bloom syndrome protein, a recq helicase. these mutations may be frameshift, missense, non-sense, or mutations of other kinds and are likely to cause deletions in the gene product. apart from helicase activity that is common to all recq helices, it also acts to prevent inappropriate homologous recombination. during replication of the genome, the two copies of dna, called sister chromatids, are held together through a structure called the centromere. during this time, the homologous (corresponding) copies are in close physical proximity to each other, allowing them to 'cross' and exchange genetic information, a process called homologous recombination. defective homologous recombination can cause mutation and genetic instability. such defective recombination can introduce gaps and breaks within the genome and disrupt the function of genes, possibly causing growth retardation, aging and elevated risk of cancer. it introduces gaps and breaks within the genome and disrupts the function of genes, often causing retardation of growth, aging and elevated risks of cancers. the bloom syndrome protein interacts with other proteins, such as topoisomerase iiiα and rmi2, and suppresses illegitimate recombination events between sequences that are divergent from strict homology, thus maintaining genome stability. individuals with bs have a loss-of-function mutation, which means that the illegitimate recombination is no longer suppressed, leading to higher rates of mutation (~10-100 times above normal, depending on cell type). ner protein-associated ps nucleotide excision repair is a dna repair mechanism. there are three excision repair pathways: nucleotide excision repair (ner), base excision repair (ber), and dna mismatch repair (mmr). in ner, the damaged dna strand is removed and the undamaged strand is kept as a template for the formation of a complementary sequence with dna polymerase. dna ligase joins the strands together to form dsdna. there are two subpathways for ner, which differ only in their mechanism for recognition: global genomic ner (gg-ner) and transcription coupled ner (tc-ner). defects in the ner pathway have been linked to progeroid syndromes. there are 28 genes in this pathway. individuals with defects in these genes often have developmental defects and exhibit neurodegeneration. they can also develop cs, xp, and ttd, often in combination with each other, as with combined xeroderma pigmentosa-cockayne syndrome (xp-cs). variants of these diseases, such as desanctis–cacchione syndrome and cerebro-oculo-facio-skeletal (cofs) syndrome, can also be caused by defects in the ner pathway. however, unlike recq-associated ps, not all individuals affected by these diseases have increased risk of cancer. all these disorders can be caused by mutations in a single gene, xpd, or in other genes. cockayne syndrome main article: cockayne syndrome cockayne syndrome (cs) is a rare autosomal recessive ps. there are three types of cs, distinguished by severity and age of onset. it occurs at a rate of about 1 in 300,000-500,000 in the united states and europe. the mean age of death is ~12 years, although the different forms differ significantly. individuals with the type i (or classical) form of the disorder usually first show symptoms between one and three years and have lifespans of between 20 and 40 years. type ii cockayne syndrome (csb) is more severe: symptoms present at birth and individuals live to approximately 6–7 years of age. type iii has the mildest symptoms, first presents later in childhood, and the cause of death is often severe nervous system deterioration and respiratory tract infections. individuals with cs appear prematurely aged and exhibit severe growth retardation leading to short stature. they have a small head (less than the -3 standard deviation), fail to gain weight and failure to thrive. they also have extreme cutaneous photosensitivity (sensitivity to sunlight), neurodevelopmental abnormalities, and deafness, and often exhibit lipoatrophy, atrophic skin, severe tooth decay, sparse hair, calcium deposits in neurons, cataracts, sensorineural hearing loss, pigmentary retinopathy, and bone abnormalities. however, they do not have a higher risk of cancer. type i and ii are known to be caused by mutation of a specific gene. csa is caused by mutations in the cross-complementing gene 8 (ercc8), which encodes for the csa protein. these mutations are thought to cause alternate splicing of the pre-mrna which leads to an abnormal protein. csb is caused by mutations in