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Essay

The Cell Nucleus and Aging: Tantalizing Clues


and Hopeful Promises
Paola Scafdi, Leslie Gordon, Tom Misteli*

T
here are a handful of biological contributing to aging. In fact, the study
questions that affect all of of some of these diseases has recently
us directly in everyday life. brought tantalizing clues as to how we
How are emotions formed, what is age. One of the most intriguing ones
the basis for consciousness, and why is a possible involvement of structural
do we look the way we do? One that components of the cell nucleus [2].
strikes particularly close to home is
the question of how we age. The sheer Aging and the Cell Nucleus
complexity of this problem has had The cell nucleus in higher organisms
many scientists throw up their hands in is now recognized as a complex,
frustration and most of the postulated highly organized repository of an
theories have been vague and generally individuals genetic information.
DOI: 10.1371/journal.pbio.0030395.g002
have involved ill-dened wear-and- The typical nucleus contains distinct
tear mechanisms. But the pursuit of functional neighborhoods made up by Figure 1. Hutchinson-Gilford Progeria
the biological basis of aging has been nonrandomly positioned chromosomes Syndrome
revitalized within the last decade by and proteinaceous subcompartments HGPS is a childhood disorder caused by
studies in yeast, worms, ies, and in which specic processes, including mutations in one of the major architectural
proteins of the cell nucleus. In HGPS patients
mice that have rmly established that gene expression, occur [3]. Which the cell nucleus has dramatically aberrant
there indeed exist specic molecular molecular mechanisms establish and morphology (bottom, right) rather than the
mechanisms that contribute to the maintain the structural integrity of uniform shape typically found in healthy
individuals (top, right).
aging process [1]. These efforts point the nucleus is largely unknown and
to several distinct, likely interrelated, represents one of the most exciting
mechanisms, ranging from improper elds in modern cell biology. Having was further strengthened by the
protein metabolism, to alterations of said that, one of the major structural observation that the localization of
specic signaling pathways, progressive elements of the nucleus, the nuclear the protein and the morphology of
damage due to generation of oxidative lamina, has been known and studied the nucleolus itself changed as yeast
free radicals, and increased genome for decades [2]. The lamina is made cells aged. However puzzling and
instability. up of A-, and B-type lamins, which are provocative these observations were, it
Although much has been learned intermediate lament proteins that was unclear whether these structural
about the aging process from simple form an interwoven network situated reorganizations were a cause or
model organisms, one intuitively at the very periphery of the nucleus consequence of aging, and it seemed
suspects that things might be somewhat underlying the nuclear membrane. a stretch to imagine that the same
different when it comes to human This structure has long been thought mechanisms might apply to human
aging. So how does one best study the to act as a shield to protect the cells.
molecular basis of human aging? The genome from mechanical stress. More
answer might be premature aging recently, this architectural feature of Citation: Scafdi P, Gordon L, Misteli T (2005) The
diseases, or progeroid syndromes. The the nucleus has also been recognized cell nucleus and aging: Tantalizing clues and hopeful
advantage of these often rare diseases as potentially playing a regulatory role promises. PLoS Biol 3(11): e395.
is that they are mostly monogenic and in gene expression because lamins This is an open-access article distributed under the
thus experimentally tractable. On the interact with chromatin and might terms of the Creative Commons Public Domain
declaration which stipulates that, once placed in the
other hand, one should keep in mind serve to anchor and organize genome public domain, this work may be freely reproduced,
that such disorders usually only mimic regions in space [2]. distributed, transmitted, modied, built upon, or
some of the features of normal aging The rst hint to a surprising otherwise used by anyone for any lawful purpose.
and it can be difcult to distinguish connection between nuclear Abbreviations: HGPS, Hutchinson-Gilford progeria
true aging symptoms from unrelated architecture and aging came from syndrome; LMNA, lamin A gene, WS, Werner syndrome
developmental defects. Regardless, it yeast, when Leonard Guarente and
Paola Scafdi and Tom Misteli are at the National
appears that progeroid syndromes may colleagues found that a protein, Cancer Institute, National Institutes of Health,
be legitimately used as model systems to Sir4, whose mutation results in Bethesda, Maryland, United States of America. Leslie
Gordon is at Brown Medical School, Providence,
investigate the physiological processes extension of life span, localizes Rhode Island, United States of America.
to the nucleolus, one of the most
prominent subcompartments of the *To whom correspondence should be addressed.
Essays articulate a specic perspective on a topic of E-mail: mistelit@mail.nih.gov
broad interest to scientists.
cell nucleus [4]. The link between
aging and nuclear organization DOI: 10.1371/journal.pbio.0030395

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Box 1. The Cell Biology of HGPS
In more than 80% of cases the gene
defect responsible for HGPS is a single
spontaneous mutation in codon 608
of the LMNA gene, which encodes
both lamin A and lamin C [6]. This base
change produces a silent amino acid
mutation and would therefore have no
consequences for the lamin A protein.
Unfortunately, the mutation activates a
cryptic splice site in LMNA, resulting in
aberrant removal of a part of the LMNA
RNA during the RNA splicing reaction
and generation of a protein lacking 50
amino acids towards its C-terminal end.
This mutant protein is referred to as
progerin. The progerin protein appears
to act in a dominant negative fashion,
and although its modus operandi
is unclear at the moment, its action
seems to be related to its extensive
post-translational modications.
Normal lamin A is produced as a pre-
lamin A protein that undergoes a
complex set of modications starting
with carboxymethylation, followed by
cleavage of the terminal three amino
acids, farnesylation at the C-terminus, and
subsequent proteolysis of its terminal
15 amino acids, leading to the removal
of the farnesyl group. Although it can
be farnesylated, pre-progerin lacks the
endoprotease recognition site necessary
for executing the nal cleavage step
and thus accumulates in a farnesylated
form [19]. Since the farnesyl group is
important for the proteins localization DOI: 10.1371/journal.pbio.0030395.g001
to the nuclear periphery, progerin
The Molecular Basis of Nuclear Defects in HGPS
accumulates in the lamina and this is
presumably where it exerts its negative
functional effects. Consistent with that notion, loss of the protease responsible for the cleavage event leads to premature aging in mice
and humans [20,21]. Given the critical importance of the lamins in nuclear architecture, it is not surprising that the cells of HGPS patient
are characterized by dramatic aberrations in nuclear architecture, particularly changes in the formation of their shape, loss of internal
heterochromatin, and changes in the distribution of numerous nuclear proteins [14,22].

Hutchinson-Gilford Progeria but die of severe atherosclerosis at emotional and developmental stages
Syndrome an average age of 13 years [7]. The are age-appropriate. A six-year-old with
initial physical signs of HGPS include HGPS may look physically like an old
The denitive proof for a causal
severe failure to thrive, heralding person, but is ready to enter rst grade
connection between nuclear
severe lipoatrophy, bony abnormalities, along with the rest of his or her peers
architecture and human aging came a small, beaked nose and receding (Figure 1). In a sense, for families and
with a stunning discovery in the mandible, complete hair loss, and friends, having a child whose mind and
summer of 2003, when the groups speckled hypopigmentation with some personality progress normally is a great
of Francis Collins and Nicolas Levy areas of tight, hard skin. As the disease fortune. In another sense, watching a
identied mutations in the lamin A progresses, vascular plaques become child whose mind is so full of promise
gene (LMNA) as the genetic cause of pervasive, leading to strokes and heart and joy experience angina, strokes, and
the segmental premature aging disease attacks. In short, these children give heart attacks that are usually reserved
Hutchinson-Gilford progeria syndrome the distinct physical impression of for the elderly is devastating.
(HGPS) [5,6] (Box 1). Children with being many decades older that they The involvement of lamin A in
HGPS usually experience normal really are. However, HGPS children are this disease was initially puzzling. It
fetal and early postnatal development neurologically unaffected, so that their is not apparent how a protein whose

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function is to maintain proper nuclear the other mechanisms because genome recombination and its main function
architecture may cause premature instability is a feature shared amongst is to reinitiate stalled replication forks.
aging. Two hypotheses rapidly emerged virtually all premature aging disorders. In the cells of WS patients, the absence
based on what cell biologists had of the WRN protein results in defective
learned about this intensely studied Genomic Instability and Aging replication, inefcient DNA repair, and
protein in the last two decades. It could The clearest link between genomic chromosome rearrangements. Thus,
be that the mutant lamin A protein instability and accelerated aging comes altered DNA metabolism in WS cells
weakens the nuclear lamina and in from a different progeroid disease, directly causes defective maintenance
that way reduces the resistance of the Werner syndrome (WS). This is an of genome integrity, and this, in turn,
cells of HGPS patients to the types of autosomal recessive disorder resulting results in cancer predisposition in
mechanical stress encountered in the from loss of function of a DNA patients [11].
body, heralding cellular dysfunction helicase, the WRN RecQ helicase [11]. The complex nature of the interplay
and death. This explanation makes Compared to HGPS, this condition has between nuclear architecture, DNA
much sense since many of the metabolism, and aging becomes clear
a later onset, with patients developing
primarily affected tissues, such as skin when considering a subset of patients
normally until puberty and showing
and vasculature, are under intense who were diagnosed with WS based on
aging symptoms in early adulthood.
mechanical stress. On the other hand, their clinical symptoms, but, puzzlingly,
Death generally occurs in the fth
recent work showing that lamins do not carry a mutation in the WRN
decade of life, mainly because of geneinstead, they have mutations
directly and indirectly interact with cancer and cardiovascular disease.
chromatin point to the possibility that in LMNA [12]. Clearly, the fact that
Extensive research over the past decade WS symptoms can be recapitulated by
changes in the lamina might lead to has shed light on the molecular and mutations in a gene that gives rise to
misregulation of sets of genes in HGPS cellular defects underlying the disease another premature aging disease is
patients. Although plausible, it is not phenotype, making WS a perfect hardly coincidental. This remarkable
obvious how the gene misregulation example of how important cell biology conuence of observations reinforces
model can account for the aging effect can be in unraveling mechanisms of the idea that HGPS and WS might
seen in patients, particularly since it has premature aging. The WRN protein share a similar underlying molecular
so far proven difcult to identify sets of is involved in DNA replication and mechanism, possibly genomic instability.
genes that are commonly misregulated
in these patients. Even the mechanical
stress model is not completely satisfying
since it is based on one of those ill-
dened wear-and-tear scenarios so
often invoked in the aging process. The
distinct possibility that aspects of both
models might apply is suggested by the
fact that several genes that respond
to mechanical signal transduction via
the cytoskeleton are affected in cells
lacking lamin A [8].
A possible breakthrough in
understanding how a structural protein
of the cell nucleus may be a key player
in aging came just a few months ago.
Zhang and colleagues discovered that
cells in HGPS patients have increased
genomic instability and DNA damage
and that the DNA repair machinery
does not function as effectively as it
does in healthy individuals [9]. In
particular, it appears that in the cells
of individuals with HGPS, the repair
machinery is not as efciently recruited
to sites of damage, and, consequently,
DNA breaks are less efciently
repaired. Although unproven at this
point, one can imagine that defects
in the lamina structure could prevent DOI: 10.1371/journal.pbio.0030395.g003
the efcient capture of repair factors
[9,10]. Admittedly, increased genome Figure 2. The DiseaseDiscoveryTherapy Cycle
instability must also be considered Diseases are clinically dened by their symptoms. The genetic basis of disease is revealed by
gene discovery. The cellular and molecular basis of a disease is characterized by cell biological
a wear-and-tear mechanism, but it approaches. These in turn provide the foundation to develop targeted therapies to alleviate
deserves more credence than some of symptoms and to fully understand the pathophysiology of the organismal disease symptoms.

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Accelerated aging, however, premature aging disorders as their These advances have put us in the
probably does not involve only genomic molecular basis is becoming well rare and desirable situation of possibly
instability. WS has also been critical in dened. The feasibility of anti-aging being able to making signicant steps
revealing a potential role of cellular intervention is made clear in the case of towards understanding one of the most
senescence in the aging process HGPS. Since the discovery of its genetic fascinating problems in biologyand
[13]. Cells entering senescence, i.e., cause less than two years ago, at least at the same time do some good for
permanent arrest of cell division, two fascinating, yet realistic, strategies patients and their families. 
undergo phenotypic changes and of molecular treatment have been
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