©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: email@example.com
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-
1. Marino G, Lopez-Otin C. Autophagy: molecular mechanisms, physiological functions and
relevance in human pathology. Cell Mol Life Sci 2004; 61:1439-54.
2. Meijer AJ, Codogno P. Signalling and autophagy regulation in health, aging and disease.
Mol Aspects Med 2006; 27:411-25.
3. Cuervo AM, Bergamini E, Brunk UT, Droge W, Ffrench M, Terman A. Autophagy and
aging: the importance of maintaining “clean” cells. Autophagy 2005; 1:131-40.
4. Marino G, Ugalde AP, Salvador-Montoliu N, Varela I, Quiros PM, Cadinanos J, van der
Pluijm I, Freije JM, Lopez-Otin C. Premature aging in mice activates a systemic metabolic
response involving autophagy induction. Hum Mol Genet 2008.
5. Navarro CL, Cau P, Levy N. Molecular bases of progeroid syndromes. Hum Mol Genet
6. Ramirez CL, Cadinanos J, Varela I, Freije JM, Lopez-Otin C. Human progeroid syndromes,
aging and cancer: new genetic and epigenetic insights into old questions. Cell Mol Life Sci
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.
USA 2005; 102:16690-5.
12. Pendas AM, Zhou Z, Cadinanos J, Freije JM, Wang J, Hultenby K, Astudillo A, Wernerson A,
Rodriguez F, Tryggvason K, Lopez-Otin C. Defective prelamin A processing and muscular
and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nat Genet 2002;
Autophagy and aging
3Autophagy2008; Vol. 4 Issue 6
7. Andressoo JO, Hoeijmakers JH. Transcription-coupled repair and premature ageing. Mutat
Res 2005; 577:179-94.
8. Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, Brewer CC, Zalewski C,
Kim HJ, Solomon B, Brooks BP, Gerber LH, Turner ML, Domingo DL, Hart TC,
Graf J, Reynolds JC, Gropman A, Yanovski JA, Gerhard-Herman M, Collins FS, Nabel EG,
Cannon RO, 3rd, Gahl WA, Introne WJ. Phenotype and course of Hutchinson-Gilford
progeria syndrome. N Engl J Med 2008; 358:592-604.
9. Varela I, Cadinanos J, Pendas AM, Gutierrez-Fernandez A, Folgueras AR, Sanchez LM,
Zhou Z, Rodriguez FJ, Stewart CL, Vega JA, Tryggvason K, Freije JM, Lopez-Otin C.
Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activa-
tion. Nature 2005; 437:564-8.
10. Scaffidi P, Misteli T. Lamin A-dependent nuclear defects in human aging. Science 2006;
11. Haithcock E, Dayani Y, Neufeld E, Zahand AJ, Feinstein N, Mattout A, Gruenbaum Y, Liu J.
Age-related changes of nuclear architecture in Caenorhabditis elegans. Proc Natl Acad Sci
13. Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J
Clin Invest 2006; 116:1776-83.
14. Hardie DG. The AMP-activated protein kinase pathway—new players upstream and down-
stream. J Cell Sci 2004; 117:5479-87.
15. Meléndez A, Tallóczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B. Autophagy genes
are essential for dauer development and life-span extension in C. elegans. Science 2003;
16. Vellai T, Takács-Vellai K, Zhang Y, Kovács AL, Orosz L, Muller F. Genetics: influence of
TOR kinase on lifespan in C. elegans. Nature 2003; 426:620.
17. Bonawitz ND, Chatenay-Lapointe M, Pan Y, Shadel GS. Reduced TOR signaling extends
chronological life span via increased respiration and upregulation of mitochondrial gene
expression. Cell Metab 2007; 5:265-77.
18. Narbonne P, Roy R. Inhibition of germline proliferation during C. elegans dauer develop-
ment requires PTEN, LKB1 and AMPK signalling. Development 2006; 133:611-9.
19. Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell 2005; 120:449-60.
20. Russell SJ, Kahn CR. Endocrine regulation of ageing. Nat Rev Mol Cell Biol 2007; 8:681-91.
21. Anderson RM, Barger JL, Edwards MG, Braun KH, O’Connor CE, Prolla TA, Weindruch R.
Dynamic regulation of PGC-1a localization and turnover implicates mitochondrial adapta-
tion in calorie restriction and the stress response. Aging Cell 2008; 7:101-11.
22. Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z,
Puigserver P. Metabolic control of muscle mitochondrial function and fatty acid oxidation
through SIRT1/PGC-1a. EMBO J 2007; 26:1913-23.
23. van de Ven M, Andressoo JO, Holcomb VB, von Lindern M, Jong WM, Zeeuw CI, Suh Y,
Hasty P, Hoeijmakers JH, van der Horst GT, Mitchell JR. Adaptive stress response in seg-
mental progeria resembles long-lived dwarfism and calorie restriction in mice. PLoS Genet
24. van der Pluijm I, Garinis GA, Brandt RM, Gorgels TG, Wijnhoven SW, Diderich KE, de
Wit J, Mitchell JR, van Oostrom C, Beems R, Niedernhofer LJ, Velasco S, Friedberg EC,
Tanaka K, van Steeg H, Hoeijmakers JH, van der Horst GT. Impaired genome maintenance
suppresses the growth hormone—insulin-like growth factor 1 axis in mice with Cockayne
syndrome. PLoS Biol 2006; 5:2.
25. Niedernhofer LJ, Garinis GA, Raams A, Lalai AS, Robinson AR, Appeldoorn E, Odijk H,
Oostendorp R, Ahmad A, van Leeuwen W, Theil AF, Vermeulen W, van der Horst GT,
Meinecke P, Kleijer WJ, Vijg J, Jaspers NG, Hoeijmakers JH. A new progeroid syndrome
reveals that genotoxic stress suppresses the somatotroph axis. Nature 2006; 444:1038-43.
26. Dechat T, Shimi T, Adam SA, Rusinol AE, Andres DA, Spielmann HP, Sinensky MS,
Goldman RD. Alterations in mitosis and cell cycle progression caused by a mutant lamin A
known to accelerate human aging. Proc Natl Acad Sci USA 2007; 104:4955-60.
27. Cao K, Capell BC, Erdos MR, Djabali K, Collins FS. A lamin A protein isoform overex-
pressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and
normal cells. Proc Natl Acad Sci USA 2007; 104:4949-54.
28. Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science
29. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk
between autophagy and apoptosis. Nat Rev Mol Cell Biol 2007; 8:741-52.
30. Espada J, Varela I, Flores I, Ugalde AP, Cadinanos J, Pendas AM, Stewart CL, Tryggvason K,
Blasco MA, Freije JM, Lopez-Otin C. Nuclear envelope defects cause stem cell dysfunction
in premature-aging mice. J Cell Biol 2008; 181:27-35.
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