Progeroid syndromes such as progeria and Werner syndrome have at least the superficial appearance of accelerated aging, but are not in fact accelerated aging. They are caused by specific breakages due to genetic mutation, usually in DNA repair mechanisms, that allow a few types of cellular dysfunction and damage to grow over time much more rapidly than is the case in unaffected individuals. Some of these types of damage are thought to be significant in normal aging, but some are clearly not present to any great degree even in very old individuals. What this should tell us is that aging is exactly an accumulation of molecular damage leading to cellular dysfunction. All forms of damage will produce outcomes that can be compared to aging, some more so than others. Whether or not this is useful in aging research depends very much on the specific details in each case.
Werner syndrome (WS) is a segmental progeria. It belongs to a small group of disorders characterized by accelerated aging. WS patients in their 20s and 30s display features similar but not identical to those of normal older individuals. WS is caused by mutations in the WRN gene, a RecQ helicase that protects genome stability by regulating DNA repair pathways and telomeres. Because of its resemblance to normal aging, WS is widely studied in the field of aging, and many consider WS the best example of an accelerated aging syndrome. The recently described hallmarks of aging pathways have been widely considered the key processes affected during aging. Since WS clinical features include many aspects of normal aging, it is not surprising that WRN functions in, or its loss impacts, many of these pathways.
Aging research has enumerated nine hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Patients with WS have defects in DNA repair machinery and show genomic instability. WRN, in association with the telomere-protecting shelterin complex, promotes telomere maintenance, and loss of WRN, as seen in vitro and in patients with WS, results in the rapid decline of telomere length. A progressive increase in DNA methylation is considered an aging biomarker, and, consistent with this, patients with WS display increased epigenetic age. Increased DNA damage accumulation, genomic instability, telomere attrition, and histone methylation are contributing factors for cellular senescence and stem cell exhaustion in WS. Although extensive research is required to sort out the molecular functions of WRN in regulating proteostasis, nutrient sensing, and mitochondria, WS is phenotypically associated with a loss in proteostasis and mitochondrial dysfunction.
Thus many of the hallmarks of aging are found in patients with WS and altered as a direct consequence of WRN loss. Although there is strong evidence for a role for WRN in several of the pathways, others show a weak association and need further investigation. Patients with WS display many aging features, but the initiating pathology for most is still not known.