Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells

Abstract

Ageing is a process that inevitably affects most living organisms and involves the accumulation of macromolecular damage, genomic instability and loss of heterochromatin. Together, these alterations lead to a decline in stem cell function and to a reduced capability to regenerate tissue. In recent years, several genetic pathways and biochemical mechanisms that contribute to physiological ageing have been described, but further research is needed to better characterize this complex biological process. Because premature ageing (progeroid) syndromes, including progeria, mimic many of the characteristics of human ageing, research into these conditions has proven to be very useful not only to identify the underlying causal mechanisms and identify treatments for these pathologies, but also for the study of physiological ageing. In this Review, we summarize the main cellular and animal models used in progeria research, with an emphasis on patient-derived induced pluripotent stem cell models, and define a series of molecular and cellular hallmarks that characterize progeroid syndromes and parallel physiological ageing. Finally, we describe the therapeutic strategies being investigated for the treatment of progeroid syndromes, and their main limitations.

Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases

“…HGPS differs from other human premature ageing syndromes by its early onset, severity of ageing symptoms and wide range of affected tissues 15,20 (TABLE 1). In contrast to HGPS, the classical adult progeria Werner syndrome is characterized by the onset of osteoporosis and cancer by the third decade of life.…”

“…In contrast to HGPS, the classical adult progeria Werner syndrome is characterized by the onset of osteoporosis and cancer by the third decade of life. The early emergence of ageing defects in patients with HGPS can be partially attributed to the dominant-negative mode of action of progerin, whereas other progeroid syndromes are often associated with recessive genetic defects that result in a loss of function of DNA repair proteins, which might be partially compensated by alternative DNA repair pathways 20 . Consequently, patients with HGPS have a wider range of tissue defects, from osteoporosis to skeletal muscle- and cardiovascular-related ageing pathologies, whereas DNA repair-associated progeroid syndromes typically involve higher cancer predisposition and, in some cases, progressive neurodegeneration 20 (TABLE 1).…”

Generation of Endothelial and Smooth Muscle Cells from Werner Syndrome-Specific Induced Pluripotent Stem Cells

“…Although the aging process strongly promotes several diseases in humans, its regulation is not fully understood. Premature aging syndromes in human show characteristics similar to those of physiological aging 43) . Understanding the molecular mechanisms of premature aging may thus help in elucidating the mechanisms of human physiological aging 44) .…”

NF-κB signaling as a driver of ageing

“…The vast majority of progeroid syndromes are a consequence of inefficient DNA repair mechanisms or defective nuclear envelope assembly, which ultimately lead to DNA damage accumulation and chromosome instability (Ramirez et al, 2007;Carrero et al, 2016). The study of progeroid syndromes requires proper experimental models to investigate different alterations and test candidate drugs (Osorio et al, 2009).…”

“…Mutations in the genes encoding lamin A or Zmpste24 (a metalloproteinase involved in the posttranslational maturation of lamin A) are responsible for several human progeroid syndromes such as Hutchinson-Gilford progeria syndrome (HGPS), atypical Werner syndrome, restrictive dermopathy, and mandibuloacral dysplasia, collectively known as progeroid laminopathies (Cau et al, 2014;Gordon et al, 2014;Carrero et al, 2016). Importantly, nuclear envelope alterations also occur during normal ageing, adding a new layer of interest to the study of these pathologies (Scaffidi and Misteli, 2006;Ragnauth et al, 2010).…”