Research Article: Accelerated aging syndromes, are they relevant to normal human aging?

Date Published: September 14, 2011

Publisher: Impact Journals LLC

Author(s): Oliver Dreesen, Colin L. Stewart.



Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in theLMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging? Much of what we know stems from the study of patient derived fibroblasts with both mutations resulting in increased DNA damage, primarily at telomeres. However, in vivo patients with Werner’s develop arteriosclerosis, among other pathologies. In HGPS patients, including iPS derived cells from HGPS patients, as well as some mouse models for Progeria, vascular smooth muscle (VSM) appears to be among the most severely affected tissues. Defective Lamin processing, associated with DNA damage, is present in VSM from old individuals, indicating processing defects may be a factor in normal aging. Whether persistent DNA damage, particularly at telomeres, is the root cause for these pathologies remains to be established, since not all progeroid Lmna mutations result in DNA damage and genome instability.

Partial Text

Age is the major risk factor in the development of many chronic medical conditions including cancer [1,2]. To enhance the well-being of an increasingly aged population, and to identify new avenues for therapeutic intervention, it is crucial that we understand the molecular basis underlying aging and age-related diseases. Aging can be defined as the “progressive deterioration of virtually every bodily function over time” [3] ultimately resulting in death. At the cellular level, aging is associated with an increase in DNA lesions, together, with defects in DNA repair mechanisms. Of particular relevance is DNA damage associated with critically shortened telomeres. Telomeres, which cap the ends of chromosomes, consist of hexameric TTAGGG repeats and the protective “shelterin” protein complex [4]. Due to the “end replication problem”, telomeres shorten during each replication cycle and critically shortened telomeres elicit a persistent DNA damage response that triggers an irreversible growth arrest (senescence). Shortened telomeres limit the regenerative capacity of tissues and are associated with increased age and a variety of medical conditions including Dykeratosis Congenita, aplastic anemia, and pulmonary fibrosis [5,6]. In germ cells, stem cells and ~85% of cancers, telomere length is maintained by telomerase, a ribonucleoprotein consisting of a reverse transcriptase (TERT) and its RNA moiety (TERC); expression of telomerase renders cells immortal.