mosaic genetic aberrations—i.e., it appears that
the relative frequency of cells from a cell clone
can first increase and then decrease later in life
( 5, 17, 18). In the present analyses, LOY was detected in ≥10% of blood cells from about 15% of
elderly males in three cohorts (figs. S3 to S5). The
cell clones with LOY were likely detectable in our
analyses because they are enriched due to an
increased proliferative potential as a consequence
of LOY, which is in agreement with chromosome
Y containing tumor suppressor genes. Recent
analysis of >8200 tumor-normal pairs suggest
that two genes (ZFY and UTY, from the male-specific part of Y) have properties of tumor
suppressors ( 19). Interestingly, both genes have
homologs on chromosome X and escape X inactivation ( 19, 20). Moreover, other analyses of various tumor collections show that chromosome Y
is lost from numerous types of tumors in frequencies ranging from 15 to 80% of cases ( 21–24).
Thus, counting both LOY in noncancerous blood
clones and in transformed tumor cells, nullisomy
Y is among the most common, if not the most
common, human mutation. The results presented
here suggest that this aneuploidy, affecting 1.6%
of the genome, is likely induced by smoking.
In conclusion, we show that LOY is more common in current smokers compared with noncurrent smokers in three cohorts (Fig. 1 and table
S1), that the effect from smoking on LOY is dose
dependent, and that this effect appears to be
transient, as it disappears after smoking cessation (Fig. 2). Epidemiological observations suggest that smoking could be a greater risk factor
for cancer outside the respiratory tract in males
compared with females (2, 4, 10). Moreover, males
have a higher incidence and mortality from most
sex-unspecific cancers ( 3, 4). The molecular mechanisms behind these observations are not well
understood, but LOY, being a male-specific, smoking-induced risk factor, could provide a missing link
and help explain these sex differences.
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We thank K. Lindblad-Toh, R. M. Myers, C.-H. Heldin, D. H. Ledbetter,
G. J. B. van Ommen, and U. Landegren for critical evaluation of
the manuscript. This study was sponsored by the Swedish Cancer
Society, the Swedish Research Council, the Swedish Heart-Lung
Foundation and Science for Life Laboratory Uppsala to J.P.D. and
the Olle Enqvist Byggmästare Foundation to L.A.F. Genotyping and
next-generation sequencing were performed by the SNP&SEQ
Technology Platform in Uppsala, Sweden, and supported by
Wellcome Trust Grants WT098017, WT064890, and WT090532,
Uppsala University, Uppsala University Hospital, the Swedish
Research Council, and the Swedish Heart-Lung Foundation. The
SNP&SEQ Technology Platform is part of Science for Life
Laboratory at Uppsala University and supported as a national
infrastructure by the Swedish Research Council. C.M.L. is
a Wellcome Trust Research Career Development Fellow
(086596/Z/08/Z). A.P.M. is a Wellcome Trust Senior Research
Fellow in Basic Biomedical Science. A.P.M. acknowledges funding
from the Wellcome Trust under awards WT064890, WT090532,
and WT098017. TwinGene was supported by the Swedish
Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-
01254 and QLG2-CT-2002-01254), NIH DK U01-066134, the
Swedish Foundation for Strategic Research (SSF), and the
Heart and Lung foundation no. 20070481. J.P.D. and L.A.F. are
cofounders and shareholders in Cray Innovation AB, as well as
co-inventors on Patent Application No. PCT/EP2014/071448,
protecting the commercial applications of LOY for the assessment
of cancer risk. Genetic variants detected in this study are
available at the Database of Genomic Structural Variation (dbVar)
under accession code nstd92 for ULSAM and PIVUS cohorts and
accession code nstd104 for the TwinGene cohort.
Materials and Methods
Figs. S1 to S6
Tables S1 to S6
References ( 25–27)
4 July 2014; accepted 24 November 2014
Published online 4 December 2014;
Lysosomal signaling molecules regulate
longevity in Caenorhabditis elegans
Andrew Folick,1 Holly D. Oakley,2, 3 Yong Yu,2, 3 Eric H. Armstrong, 4 Manju Kumari, 5*
Lucas Sanor,2 David D. Moore,1, 6 Eric A. Ortlund, 4 Rudolf Zechner, 5 Meng C. Wang1,2, 3†
Lysosomes are crucial cellular organelles for human health that function in digestion and recycling
of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that
affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL- 4 triggered
nuclear translocalization of a lysosomal lipid chaperone LBP- 8, which promoted longevity by
activating the nuclear hormone receptors NHR- 49 and NHR- 80. We used high-throughput
metabolomic analysis to identify several lipids in which abundance was increased in worms
constitutively overexpressing LIPL- 4. Among them, oleoylethanolamide directly bound to LBP- 8
and NHR- 80 proteins, activated transcription of target genes of NHR- 49 and NHR- 80, and
promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway
that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.
Lysosomes contain acid hydrolytic enzymes, digesting macromolecules taken up by en- docytosis and recycling dysfunctional cel- lular components during autophagy (1). Lysosomal deficiency is associated with
human diseases. For example, loss of human
lysosomal acid lipase, LIPA, results in severe systemic metabolic malfunction known as infantile
Wolman disease (2). Here, we explored how lysosomes might generate signaling molecules that
regulate aging by influencing nuclear transcription.
We analyzed a Caenorhabditis elegans longevity-promoting lipase, LIPL- 4, which has sequence
and functional similarities with human LIPA
(fig. S1). Lipid hydrolase activity was decreased in
lipl- 4(tm4417) loss-of-function mutants at pH 4. 5
but not at pH 7. 4 (Fig. 1A). FLAG-tagged LIPL- 4
protein was localized to intestinal lysosomes
(Fig. 1, B to D, and fig. S2). Increased lipl- 4 expression is associated with longevity ( 3). A transgenic
strain (lipl- 4 Tg) that constitutively expressed lipl- 4
in the intestine had 55% mean life-span increase
compared with wild-type (WT) animals (Fig. 1E
and table S1) and delayed age-related decline of
physical activity (fig. S3A). Constitutive expression
of LIPL- 4 without the signal peptide (lipl- 4 Tg no
SP), which was not targeted to the lysosome,
caused little extension of life span (fig. S4 and
table S1), which suggests that the lysosomal activity of LIPL- 4 is essential for its longevity effect.
To elucidate whether lipid signals are affected by
the LIPL- 4 lipase, we examined fatty acid–binding
proteins (FABPs) that are intracellular lipid chaperones shuttling lipid molecules between cellular
SCIENCE sciencemag.org 2 JANUARY 2015 • VOL 347 ISSUE 6217 83
1Program in Developmental Biology, Baylor College of
Medicine, Houston, TX 77030, USA. 2Huffington Center on
Aging, Baylor College of Medicine, Houston, TX 77030, USA.
3Department of Molecular and Human Genetics, Baylor
College of Medicine, Houston, TX 77030, USA. 4Department
of Biochemistry, Discovery and Developmental Therapeutics,
Winship Cancer Institute, Emory University School of
Medicine, Atlanta, GA 30322, USA 5Institute of Molecular
Biosciences, University of Graz, Graz, A-8010, Austria.
6Department of Molecular and Cellular Biology, Baylor
College of Medicine, Houston, TX 77030, USA.
*Present address: Division of Endocrinology, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA 02215, USA.
†Corresponding author. E-mail: email@example.com
RESEARCH | REPORTS