©2008 Landes Bioscience. Do not distribute.
[Autophagy 4:6, 1-3; 16 August 2008]; ©2008 Landes Bioscience
1Autophagy2008; Vol. 4 Issue 6
This manuscript has been published online, prior to printing.Once the issue is complete and page numbers have been assigned, the citation will change accordingly.
It is widely-assumed that the autophagic activity of living cells
decreases with age and probably contributes to the accumulation
of damaged macromolecules and organelles during aging.1-3 Over
the last few years, the study of segmental progeroid syndromes in
which certain aspects of aging are manifested precociously or in
exacerbated form, has increased our knowledge of the molecular
basis of aging. We have recently reported the unexpected finding
that distinct progeroid murine models exhibit an extensive basal
activation of autophagy instead of the characteristic decline in
this process occurring during normal aging.4 Further studies
on Zmpste24-null progeroid mice, which are a reliable model
of human Hutchinson-Gilford progeria, have revealed that the
observed autophagic increase is associated with a series of metabolic
alterations resembling those occurring under calorie restriction or
in other situations reported to prolong lifespan.4 Here, we analyze
these unexpected findings and discuss their possible implications
for the development of premature aging.
Although the precise molecular determinants of aging are still
very far from being completely understood, our knowledge of the
molecular basis of this complex process has improved considerably,
in part due to the study of segmental progeroid syndromes. These
syndromes are dramatic diseases in which certain features of human
aging are prematurely developed.5 Progeroid syndromes can be clas-
sified into two major groups attending to their underlying molecular
defects.6 The first group comprises disorders in which alterations
in genome-stability maintenance mechanisms lead to the develop-
ment of premature aging, whereas the second group includes those
syndromes caused by defects in the nuclear envelope architecture.7-9
In the last few years, the study of animal models of accelerated aging
has yielded interesting results which have contributed to extend our
knowledge of the molecular basis of normal aging.10,11 However,
no studies about autophagic activity in progeria patients or animal
models showing accelerated aging had been previously reported.
On this basis, together with the increasing connections between
autophagy and aging, we decided to check the basal autophagic
activity in progeroid murine models caused by either defects in
DNA repair machinery or alterations in the nuclear envelope struc-
ture. Surprisingly, our analyses have revealed that progeroid mice fed
ad libitum present a clear increase in their tissue autophagic activity
as compared with the corresponding controls, independently of the
molecular alterations underlying their phenotype.4 This unexpected
finding prompted us to study the molecular determinants of this
autophagy increase. For this purpose, we focused our analysis on
mice deficient in Zmpste24 metalloproteinase (Fig. 1), which show
accelerated aging and are a model of human Hutchinson-Gilford
progeria.9 These mice present major alterations in nuclear structure
due to a defect in the processing of lamin A, an essential constituent
of the nuclear envelope.12 We found that the observed autophagy
increase is associated with mTOR inhibition and the upregulation
of LKB1-AMPK axis activity (Fig. 1). In addition, these alterations
were linked to significant changes in biochemical parameters, such
as reduced levels of blood glucose, insulin and leptin, together with
an increase in plasma adiponectin levels.4 These alterations could
explain the elevated LKB1-AMPK activity observed in progeroid
mice as well as the reported mTOR inhibition and autophagy
activation. In fact, a decrease in blood glucose levels or an increase
of circulating adiponectin lead to an in vivo induction of AMPK
activity,13 which in turn inhibits mTOR activity.14 Since all these
alterations in blood parameters point to a deregulation of glucose
and lipid homeostasis, we checked the transcriptional levels of
key genes for these processes in Zmpste24-/- mice livers, as this
tissue is a major modulator of glucose and lipid homeostasis in
vivo. Our analyses revealed the existence of a complex metabolic
shift in glucose and lipid metabolism, as assessed by the finding
that key genes involved in gluconeogenesis, glycogen accumula-
tion, fatty acid synthesis, and β-oxidation were clearly upregulated
in mutant mice.4 These metabolic alterations were linked to a
substantial increase in the levels of hepatic glycogen and also to the
presence of liver steatosis (retention of lipids in cells), confirming
the occurrence of a profound metabolic shift in glucose and lipid
homeostasis, which likely underlies the observed basal autophagy
increase, mTOR inhibition and LKB1-AMPK axis upregulation in
*Correspondence to: Carlos Lopez-Otin; Departamento de Bioquímica y Biología
Molecular; Facultad de Medicina; Universidad de Oviedo; Oviedo 33006 Spain;
Tel.: 34.985.104201; Fax: 34.985.103564; Email: firstname.lastname@example.org
Submitted: 05/19/08; Revised: 06/12/08; Accepted: 06/20/08
Previously published online as an Autophagy E-publication:
Addendum to: Mariño G, Ugalde AP, Montoliu NS, Varela I, Quirós PM, Cadiñanos
J, van der Pluijm I, Freije JM, Otín CL. Premature aging in mice activates a systemic
metabolic response involving autophagy induction. Hum Mol Genet 2008; In Press.
Autophagy and aging
New lessons from progeroid mice
Guillermo Mariño and Carlos López-Otín*
Departamento de Bioquímica y Biología Molecular; Facultad de Medicina; Instituto Universitario de Oncología; Universidad de Oviedo; Oviedo, Spain
Key words: autophagy, aging, progeria, tor, calorie restriction
©2008 Landes Bioscience. Do not distribute.
activation facilitates temporary adaptation to metabolic stress, this
catabolic pathway may also lead to cell death when chronically
activated.28,29 This situation could contribute to the progressive
muscular and cardiac wasting observed in both progeroid mice
Autophagy and aging
It is remarkable that the majority of the detected
alterations in these progeroid mice are associated
with longer lifespan rather than with the short-
ened longevity characteristic of these progeroid
animals. In fact, autophagic activity is essential
for dauer development and lifespan extension in
Caenorhabditis elegans15 and a downregulation of
TOR-signaling extends lifespan in both yeast and
nematodes.16,17 Similarly, AMPK overexpression
promotes longevity in C. elegans18 and the metabolic
alterations found in progeroid mice, as hypoinsu-
linemia and hypoglycaemia, increase lifespan in
diverse model organisms.19,20 In addition, many
of the transcriptional alterations observed in key
genes for glucose and lipid metabolism regulation
resemble those observed in animals subjected to
calorie restriction.21,22 In this regard, very recent
studies show that progeroid mice with defects in
different DNA repair genes also exhibit an adaptive
metabolic response characterized by an upregulation
of gluconeogenic and β-oxidative pathways as well as
by alterations in the glucose/insulin pathway, which
resemble in many aspects the changes observed in
Zmpste24-null mice.23-25 Our novel observation that
autophagy is also markedly induced in these prog-
eroid models suggests that activation of this pathway
might be part of a general metabolic shift occurring
in different progeroid syndromes.
Taken together, all these observations suggest that the different
molecular defects leading to the development of premature aging
trigger a complex and conserved metabolic response including many
features tightly associated with lifespan extension. At first sight, this
fact seems intriguing. However, most of these features point towards
a reduction in the metabolic activity of the organism, which inevi-
tably leads to a reduction in cell division rate. This appears to be an
adequate strategy to reduce the accumulation of cellular damage,
as it has been reported that cell division drastically increases the
rates of abnormal chromosome segregation and binucleation in cells
from Hutchinson-Gilford progeria patients.26,27 Thus, it is reason-
able to think that a normal growth rate would compromise somatic
integrity in progeroid animals. In this case, a metabolic response
aimed at reallocating resources from growth to somatic preserva-
tion could be the best way to attenuate the consequences of the
molecular alterations underlying progeroid syndromes. However, it
is clear that this adaptive response fails to counteract the mentioned
alterations, which irreversibly lead to the premature death observed
in progeroid mice.
The paradoxical finding that autophagy is upregulated in progeroid
mice (Fig. 1) may also help to understand the mechanisms under-
lying the multiple tissue alterations observed in these syndromes.
Although the observed metabolic shift could be beneficial, it could
also be detrimental for the organism if overactivated (Fig. 2). In this
regard, we must take into account the fact that although autophagy
and progeria patients.8,12 However, this hypothesis has to be tested
using specific autophagy inhibitors or appropriate animal models of
autophagy-deficiency, which are currently unavailable. These further
studies will be helpful to clarify whether the observed increase
of autophagic activity in progeroid mice helps to slow down the
effects of the molecular alterations leading to premature aging, or by
contrast, contributes to the development of the multiple pathologies
observed in these mice. In this latter case, the autophagy pathway
could be a future clinical target which may help to improve the prog-
nosis of progeria patients.
We thank Drs. J.P. Freije and I. Varela for helpful comments.
Our work is supported by grants from Ministerio de Educación y
Ciencia-Spain, Fundación “M. Botín”, Fundación Lilly, and the
European Union (FP6 Cancer Degradome and FP7). The Instituto
Universitario de Oncología is supported by Obra Social Cajastur-
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Figure 1. Summary of the most representative autophagy-related alterations observed in
progeroid mice. (A) Zmpste24-/- mice, which show premature aging features as compared to
aged-matched wild-type littermates (up), present a basal autophagy increase when compared
to their wild-type littermates (down). (B) Representative immunoblots of the autophagy-related
alterations observed in Zmpste24-/- mice.
©2008 Landes Bioscience. Do not distribute.
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Figure 2. Proposed model for the connections between autophagy and
premature aging. The nuclear structure alterations or the accumulation of
DNA damage underlying most progeroid syndromes lead to the activation of
diverse stress responses, including p53 signaling and stem cell dysfunction,
which are both associated with the development of premature aging.9,30 On
the other hand, most changes derived from the metabolic shift observed in
progeroid mice probably contribute to slow down the development of aging
features.4,25 However, whether the role played by constitutively activated
autophagy is beneficial or detrimental in progeroid syndromes remains