R E V I E W Model of human aging: Recent ﬁndings on Werner’s and Hutchinson-Gilford progeria syndromes Shian-ling Ding1 Chen-Yang Shen2,3,4 1Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, Taiwan; 2Institute of Biomedical Sciences, and 3Life Science Library, Academia Sinica, Taipei, Taiwan; 4Graduate Institute of Environmental Science, China Medical University, Taichong, Taiwan Correspondence: Shian-ling Ding Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, 11485,Taiwan Tel +886 2 26321181 ext 257 Fax +886 2 23649857 Email slding@knjc.edu.tw 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, result- ing 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. Keywords: human aging, Hutchinson-Gilford Progeria syndrome, Werner syndrome Introduction Aging is an extremely complicated process and is known to be driven by a variety of different mutually interacting mechanisms. Conventionally, it is seen as a process of progressive failure of homeostasis involving genes for maintenance and repair, environmental factors leading to molecular damage and molecular heterogeneity, and chance events with potentially signiﬁcant consequences for death (Alberts et al 2002). Since several human progeroid synqdromes (PSs) (human premature aging-like syndromes) are characterized by features resembling precocious aging, the identiﬁca- tion of the genes involved in PSs has provided important clues to understanding the molecular mechanisms underlying normal human aging (Hutchinson 1886, Gilford 1904; Martin 1978, 1985). The classic example of PS is Werner’s syndrome (WS), a progeria of the adult, which is caused by a mutation in a gene coding for a member of the RecQ helicase family, WRN (Yu et al 1996) and is characterized by features resembling preco- cious aging, appearing as a variety of visible features associated with aging, such as graying of the hair and skeletal changes, which occur much earlier than normal (Goto 1997). WRN acts as a “caretaker of the genome” and functions in both DNA repair and transcription, suggesting that breakdown of these processes is critical in promoting aging (Epstein et al 1966; Goto 1997; Bachrati et al 2003). Hutchinson- Gilford progeria syndrome (HGPS), a progeria of the child, is the other classic example, and is caused by mutations in the gene LMNA (1q21.2) (Eriksson et al 2003), encoding a nuclear envelope protein, lamin A, which has been shown to affect RNA polymerase II transcription, probably by alterations in chromatin organization Clinical Interventions in Aging 2008:3(3) 431–444 © 2008 Dove Medical Press Limited. All rights reserved 431