Integrity matters: Linking nuclear architecture to lifespan
Daily choices, of food, activity level, sun exposure, can positively influence the chance of living a long healthy life. Through these choices, we apparently influence some of the same biochemical and genetic pathways that regulate lifespan in lower eukaryotes. For example, conserved genes that regulate insulin/IGF-1 signaling and oxidative stress responses control longevity in Caenorhabditis elegans, Drosophila, and mice (1). The genetic control of lifespan is conserved in metazoan evolution, as first shown by classic studies with the nematode C. elegans (2). Lifespan and aging in mammals also may be influenced by the efficiency of DNA repair and replacement of damaged tissue by stem cells (1). Because aging is a complex phenomenon, and because lifespan can be shortened by many extraneous factors (e.g., toxins, bad genes, bad driving), the litmus test for truly aging-relevant pathways has been whether mutations in these pathways can extend lifespan. In contrast, lifespan is reduced in Hutchinson–Gilford progeria syndrome (HGPS) and other human “accelerated aging” (progeria) syndromes, leading to ongoing debate as to whether these syndromes can provide insight into the mechanisms of normal aging (1, 3). New findings in C. elegans, the classic model organism for aging, now reveal a fundamental link between lifespan and the nucleus. In a key breakthrough, Haithcock et al. (4), in a recent issue of PNAS, showed that normal aging in C. elegans involves progressive stochastic (cell-by-cell) deterioration of nuclear lamina and chromatin architecture in most tissues except neurons. In animals with reduced lifespan due to the FOXO transcription factor mutation daf-16(mu86), these changes in nuclear shape and heterochromatin loss occurred correspondingly early (4, 5). Most strikingly, in animals with extended lifespan due to the well characterized insulin receptor mutant daf-2(e1370), the deterioration of nuclear architecture was delayed (4, 6). Thus, extended lifespan correlated with extended nuclear envelope integrity. Further work showed that molecules central to nuclear architecture and nuclear assembly, namely lamin filaments and LEM-domain nuclear membrane proteins, are required to achieve a normal lifespan. Lifespan was shortened in animals with postembryonically reduced expression of lmn-1, the only lamin gene in C. elegans (4). Lifespan also was shortened in animals with postembryonic reductions of both emr-1 and lem-2, which encode lamin-binding nuclear membrane proteins named Ce-emerin and Ce-MAN1, respectively (4). Ce-emerin and Ce-MAN1 belong to the LEM-domain family of nuclear proteins and are conserved in humans (ref. 7 and references therein).
Vertebrate lamins and LEM-domain proteins are involved in gene regulation, TGFβ signaling, DNA replication, and mRNA transcription, and they also have fundamental roles in chromatin organization, nuclear architecture, and nuclear assembly (8). Previous studies showed that C. elegans embryos down-regulated for Ce-lamin (9), Ce-emerin plus Ce-MAN1 (10), or their mutual binding partner Barrier-to-Autointegration Factor (11) all died around the 100-cell stage with similar defects in nuclear structure and chromatin organization. Haithcock et al. (4) propose that nuclear lamina integrity is linked to enhanced lifespan and that compromised nuclear architecture could be a central cause of aging in nonneuronal tissues (see Fig. 1).
New findings link the integrity of the nuclear lamin filament network (lamina) to lifespan in C. elegans. These findings suggest that the mechanisms of human accelerated aging disorders such as Hutchinson–Gilford progeria syndrome, caused by mutations in A-type lamins, are relevant to aging.
These findings come at an exciting time. Research on the nuclear envelope and its attached network of A- and B-type lamin filaments is blossoming. Interest in this field is being fueled by the staggering variety of tissue-specific diseases and syndromes (“laminopathies”) caused by mutations in LMNA, the gene encoding A-type lamins (12). HGPS is caused by a mutation that causes missplicing of the lamin A mRNA (13). Children with HGPS are born normal, but within 1 year their growth slows significantly, and they begin developing a constellation of phenotypes including cardiovascular disease, which leads to death at an average age of 13 years (3). The mRNA splicing defect caused by most HGPS mutations deletes 50 residues in the C-terminal “tail” domain of lamin A and also blocks proteolytic cleavage of the farnesylated C-terminal peptide of the lamin A precursor (13). The resulting molecule accumulates at the inner nuclear membrane and is toxic to nuclear architecture: it aggregates wild-type lamins, grossly disrupts nuclear shape, and results in a loss of heterochromatin in cultured HGPS fibroblasts (14). Similar changes in nuclear structure are seen during normal aging in C. elegans (4).
Results from several systems (C. elegans, Drosophila, Xenopus egg extracts, and cultured mammalian cells) suggest that basic activities including gene regulation, cell signaling, DNA replication, chromatin organization, and cell proliferation depend directly or indirectly on the nuclear lamina network (15). Why and how each activity is lamin-dependent are major open questions, but current evidence supports the idea that lamin filaments provide scaffolds for the assembly, regulation, function, sequestration, or mechanical reinforcement of many different proteins and protein machines in the nucleus that regulate gene expression and other activities (8). One can speculate that the aging-relevant insulin signaling and stress response pathways might “use” lamins similarly to regulate gene expression.
The new report (4) and a previous report by Herndon et al. (16) are thought-provoking for an additional reason: if lamins are so important in all cells, as extrapolated from current knowledge, then why are neurons spared? Neurons do not deteriorate structurally during normal aging in C. elegans (4, 16). Extending this theme, children with HGPS have normal intelligence and normal emotional development (3). The nuclear lamina network has not been studied in the brain. Differences in the way lamins are expressed or used in the brain might provide new clues about the mechanisms of aging and laminopathies. Brain neurons differ profoundly from tissues susceptible to “accelerated aging” in at least one major respect: brain neurons are sheltered from mechanical forces by the skull. In contrast, HGPS (and most other laminopathies) appears to strike primarily the connective tissues (e.g., bone, cartilage, tendons, joints, fat, and muscle) (12, 17), which derive from mesenchymal stem cells (ref. 18 and references therein). Connective tissue cells create, transmit, resist, regulate, and respond to mechanical forces. Interestingly, lamin A and emerin are both required for mechanosensitive gene expression in cultured mouse fibroblasts (ref. 19 and references therein). By linking the integrity of the nuclear “lamina” network, specifically lamins and LEM-domain proteins, to extended lifespan, Haithcock et al. (4) have taken this exciting field to a new level. Further work on lamins and nuclear architecture may provide novel insights into how longevity pathways influence lifespan and nuclear architecture (20), the mechanisms of tissue degeneration that plague normal aging, and why mechanosensitive tissues deteriorate so rapidly in HGPS and other laminopathies.
Footnotes
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↵ * To whom correspondence should be addressed at: Department of Cell Biology, WBSB Room G-10, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205. E-mail: klwilson{at}jhmi.edu.
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Author contributions: K.L.W. wrote the paper.
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Conflict of interest statement: No conflicts declared.
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See companion article on page 16690 in issue 46 of volume 102.
- Copyright © 2005, The National Academy of Sciences
