In certain premature-ageing syndromes, the architecture of the cell nucleus is abnormal. An animal model shows similar malformations during normal ageing, corroborating the idea that genome instability underlies ageing.
Hutchinson–Gilford progeria syndrome (HGPS) produces signs of dramatically accelerated ageing, such as early cessation of growth, baldness at the age of two, progressive degeneration of the skin, muscle and bone, and often fatal atherosclerosis (arterial plaque build-up) in childhood. Like many other premature-ageing syndromes, HGPS does not recapitulate all aspects of ageing — for example, patients show no neurodegeneration or cancer predisposition. HGPS and several other degenerative disorders are linked to defects in proteins that maintain the shape and organization of the nucleus, hinting that deteriorations in nuclear architecture may underlie some features of ageing. This notion is borne out by Haithcock et al.1, who report in Proceedings of the National Academy of Sciences that progressive malformation of nuclei occurs with age in a classic animal model of ageing.
HGPS is associated with mutations in the nuclear protein lamin A (refs 2, 3). Lamin proteins polymerize to form an intranuclear scaffold known as the lamina, particularly around the edge of the nucleus. This lamina supports the nuclear architecture and helps to organize nuclear processes such as DNA and RNA synthesis4,5. A remarkable diversity of degenerative human disorders is linked to different mutations in lamin A: so far, 11 so-called laminopathies are known, several of which involve premature ageing (Table 1). The common HGPS mutation results in a deletion of 50 amino acids from the protein, and gradual accumulation of the truncated, abnormal lamin A probably affects lamina function. The cells of HGPS patients show progressive abnormalities in nuclear shape, including a folded nuclear envelope and loss of peripheral heterochromatin — the densely packed DNA that is normally found in a dim rim underlying the nuclear lamina3,6. This link between mutated lamin A and premature ageing does not, however, prove a causal role for nuclear architecture in normal ageing. In fact, the relevance of premature-ageing syndromes to normal ageing is highly controversial7.
To find out whether changes in nuclear shape are associated with normal ageing, Haithcock et al.1 turned to an animal model often used in ageing research: Caenorhabditis elegans, a nematode worm that is well known for its extreme-longevity mutants. The mean lifespan of this nematode is only two to three weeks, but it can be extended more than five times by downregulating the insulin/IGF-1 signalling pathway. This pathway controls metabolism and influences ageing rate in all organisms investigated, including mammals8. To visualize the nuclear lamina, the authors engineered a worm in which the single gene for lamin was fused to a gene encoding green fluorescent protein. The fluorescent lamin protein revealed age-related, progressive changes in nuclear lamina morphology in all cells except neurons and gametes. Whereas in young animals the lamin protein was properly distributed around the nuclear periphery, with ageing its distribution became progressively irregular. Concomitantly, the nuclear shape changed and peripheral heterochromatin disappeared. Variations between animals and among cells underscored the stochastic nature of the changes.
Notably, the kinetics of the nuclear alterations seemed to be under the control of the insulin/IGF-1-like signalling system: the onset of severe nuclear morphological change was delayed in two long-lived C. elegans mutants, and it was correspondingly advanced in two short-lived animals. So, the nuclear changes seem to be connected with the normal ageing process. Although still correlative, these intriguing findings are highly reminiscent of progressive nuclear alterations found in cells of rapidly ageing HGPS patients6 and in cells of naturally aged mammals9. This supports the parallel between ageing — whether normal, accelerated or delayed — and malformation of nuclei.
How can the accumulation of abnormal lamin A contribute to ageing? There are several hypotheses4,5. Structurally, lamin A dysfunction might make the nucleus more vulnerable to mechanical stress. Although appealing, this cannot be the only explanation because not all tissues affected in HGPS patients are subject to abnormal levels of mechanical stress (for example, fat tissue). Alternatively, lamin A interacts with a diverse array of gene regulatory factors, including pRB, which controls entry into the cell-division cycle and the balance between cell division and specialization. Accumulation of truncated lamin A may mean that its binding partners end up in the wrong place and disrupt their regulatory function, thereby promoting permanent growth arrest (senescence).
We would like to propose another option. Lamin A indirectly influences genome stability because the nuclear lamina is involved in processes such as replication and gene expression10, and these processes are intimately linked with the signalling that follows DNA damage and DNA repair. Consequently, replication-associated repair (such as homologous recombination and mismatch repair), damage- tolerance mechanisms (such as translesion synthesis) and DNA-damage signalling may be compromised when the nuclear lamina is dysfunctional. Similarly, the transcription of genes is linked with the lamina and transcription-coupled repair is associated with the nuclear matrix11. This repair pathway promotes cell survival by allowing recovery of gene expression blocked by damage in the DNA template.
DNA damage inevitably occurs with time; for example, because oxidative respiration continually generates highly reactive oxygen species. So, the following sequence of events may be envisaged (Fig. 1). Disruption of the nuclear lamina compromises several DNA repair pathways. This triggers cell death and senescence upon damage induction, thereby promoting ageing. In support of this idea, there are signs of genome instability in HGPS cells and mouse mutants12. Additionally, mice with abnormal lamin A exhibit spontaneous activation of p53 protein, the guardian of genome integrity13. This would add the progeroid laminopathies to the growing list of other progeroid syndromes — which lead to accelerated ageing — that are all linked with impaired genome stability (Table 1).
This scenario may explain the connection between lifespan extension and insulin/IGF-1 signalling and caloric restriction, because oxidative metabolism is a substantial cause of DNA damage: the lower or more efficient oxidative respiration is, the fewer harmful reactive oxygen species are produced, and the longer the lifespan is. This could account for why screens for mutants that have extended lifespans have never yielded genes associated with DNA repair. Apart from the fact that improving repair by single mutations is difficult, it would be impossible to improve many distinct repair systems simultaneously. Only numerous small evolutionary steps over long periods of time would eventually result in longer lifespan. However, the rate of metabolism is under the control of the single IGF-1 pathway, explaining why single mutants that reduce or enhance the rate of metabolism in general can retard or accelerate ageing, respectively, by regulating the cause of DNA damage.
Because genome stability in toto, including nuclear lamina function, covers almost all ageing features displayed in the wide spectrum of progeroid disorders, it is currently the most consistent parameter to underlie ageing. Thus, accelerated-ageing syndromes may be as significant for insight into normal ageing as cancer predisposition conditions have been for understanding cancer. Similarly, DNA damage may be as relevant for ageing as it is now recognized to be for cancer.
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