Model of human aging: Recent findings on Werner’s and Hutchinson-Gilford progeria syndromes

Abstract

The molecular mechanisms involved in human aging are complicated. Two progeria syndromes, Werner’s syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS), characterized by clinical features mimicking physiological aging at an early age, provide insights into the mechanisms of natural aging. Based on recent findings on WS and HGPS, we suggest a model of human aging. Human aging can be triggered by two main mechanisms, telomere shortening and DNA damage. In telomere-dependent aging, telomere shortening and dysfunction may lead to DNA damage responses which induce cellular senescence. In DNA damage-initiated aging, DNA damage accumulates, along with DNA repair deficiencies, resulting in genomic instability and accelerated cellular senescence. In addition, aging due to both mechanisms (DNA damage and telomere shortening) is strongly dependent on p53 status. These two mechanisms can also act cooperatively to increase the overall level of genomic instability, triggering the onset of human aging phenotypes.

Theories of Human Aging of Molecules to Society

“…The classic example of progeroid syndrome Werner syndrome is an adult progeria caused by a mutation of the gene encoding the RecQ helicase, with the appearance of visible signs of aging such as skeletal changes and graying of hair early age and premature death [33,34]. Syndrome Hutchinson-Gilford progeriais a child progeria, a rare genetic disorder first described by Jonathan Hutchinson in 1886 and Hastings Gilford in 1897.…”

“…It is characterized by premature aging phenotype with involvement of skin, bones, heart and blood vessels. Patients have the appearance of "plucked bird" and die prematurely from cardiovascular disease in the second decade of life [33,35,36].…”

Understanding the molecular basis of common fragile sites instability: Role of the proteins involved in the recovery of stalled replication forks

“…All these syndrome, which are characterized by elevated genomic instability. 70,71 We recently demonstrated that loss of WRN induces accumulation of chromosome gaps and breaks specifically at CFS even under unperturbed conditions. 65 In addition, exposure of cells to low doses of aphidicolin leads to extensive relocalization of WRN to nuclear foci in replicating cells.…”

Oxidative stress and antioxidant response in fibroblasts from Werner and Atypical Werner Syndromes

“…The cells of these patients are prone to cellular senescence and neoplastic transformation and have an elevated genomic instability [7, 8] and sensibility to DNA damage induced by oxidative stress [4, 9]. …”