2 JANUARY 2015 • VOL 347 ISSUE 6217 33 SCIENCE sciencemag.org
activate these nuclear hormone receptors
and promote longevity. OEA may therefore
represent a key ligand that activates these
nuclear receptors to modulate aging, although it remains to be determined whether
OEA affects aging entirely by acting through
these transcription factors or whether it has
other effects on the organism. The ensemble
of target genes downstream of these nuclear
receptors that promote longevity also remains to be identified.
The findings of Folick et al. are exciting because they are the first to establish a
lysosome-to-nucleus signal that functions in
aging regulation and to show that dietary
modulation of fatty acids such as OEA has
the potential to delay aging. Because genes
in this pathway are conserved, the findings
also provide insights on the regulation of human nuclear receptors by lysosomal signaling. Given that OEA affects feeding behavior
and body weight in mice by acting through
PPARα ( 8), dietary OEA may also have an impact on aging in mammals. The availability of
bioactive lipids such as OEA could depend on
the internal nutritional state of the organism.
Environmental interventions such as fasting
or overfeeding could alter the availability and
composition of the lipid pool, consequently
changing the binding status of nuclear receptors, altering downstream transcription programs, and affecting aging.
Signaling between the lysosome and the
nucleus is likely to be a two-way street.
Indeed, recent reports in mammalian
cells have established that lysosomal autophagy can be regulated by lipid-sensing
transcription factors in the nucleus during
the feeding and fasting cycles, namely the
transcription factors farnesoid X receptor
(FXR) ( 11), cyclic adenosine monophosphate responsive element binding protein
(CREB) ( 11), and PPARα ( 12). Thus, while
lysosomes release diffusible lipid messengers that affect transcription, lipid-sensing
transcription factors could provide feedback regulation of the lysosome, maintaining metabolic homeostasis based on
Lysosomes are involved in controlling
the activity of mTOR and the execution
of autophagy (an intracellular mechanism
that breaks down cellular components)
in response to nutrient availability ( 13).
LIPL- 4 itself is important for inducing
autophagy in C. elegans ( 6). Therefore, a
key remaining question concerns the con-
nection between this lysosome-to-nucleus
signaling and the TOR-autophagy path-
way. Could TOR and autophagy play a role
in the longevity of LIPL- 4–overexpressing
animals? Conversely, does an increase in
OEA extend life span because of inhibition
of the TOR pathway? More generally, it will
be important to determine
whether this lysosome-to-
nucleus signaling pathway
is important for longevity
conditions that have been
shown to require LIPL- 4,
such as the lack of an intact
germ line ( 5, 6).
In a broader context, these
findings raise the question
of the site of action of this
lysosome-to-nucleus signaling pathway and whether it
is entirely cell-autonomous.
Both LIPL- 4 and LBP- 8 are
expressed in the gut of the
worm, and presumably this is
also the site of action of OEA.
However, an interesting possibility could be that OEA,
as a cell-permeable lipid, is
secreted outside the gut to
activate nuclear receptors in
other tissues. In this way, an
inter-tissue lipid signaling
network may exist during
the aging process and might
be involved in systemic life-span regulation ( 14).
In addition to OEA, other
lipids or metabolites could
act as diffusible signals between different organelles to orchestrate
coordinated cellular responses. Unbiased
metabolomic profiling is a promising discovery tool to decipher the mechanisms underlying many human metabolic diseases.
This approach would also help to identify
the elusive ligands for many nuclear receptors ( 15). Ultimately, modulations of bioactive lipids could be a therapeutic strategy
for a wide range of human metabolic disorders and age-related diseases. ■
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( LIPL- 4)
Lysosome LIPL- 4
A pathway to longevity. (A) During normal aging, the lipase LIPL- 4 and lipid-binding protein LBP- 8 reside in the lysosome. (B) In
long-lived worms, there is an increase in LIPL- 4 and the fatty acid OEA in the lysosome. OEA translocates into the nucleus by binding to
the chaperone LBP- 8. OEA binds to the nuclear receptor NHR- 80 to affect the expression of genes that regulate longevity. (C) Nutrient
status could also affect LIPL- 4 activity. A positive feedback loop likely exists between nuclear transcription factors and the lysosome. The
m TOR and autophagy pathways could modulate this lysosome-to-nucleus pathway for longevity.
10.1126/science.aaa4565 I L L U S T