1050 Biochemical Society Transactions (2009) Volume 37, part 5

A novel function of lipid droplets in regulating

longevity
Alexander A. Goldberg1 , Simon D. Bourque1 , Pavlo Kyryakov1 , Tatiana Boukh-Viner, Christopher Gregg, Adam Beach,
Michelle T. Burstein, Gayane Machkalyan, Vincent Richard, Sonia Rampersad and Vladimir I. Titorenko2
Department of Biology, Concordia University, 7141 Sherbrooke Street, West, SP Building, Room 501-9, Montreal, QC, Canada, H4B 1R6

Abstract
Growing evidence supports the view that LDs (lipid droplets) are dynamic organelles that can serve both as an
intracellular signalling compartment and as an organizing platform orchestrating many vital processes in eu-
www.biochemsoctrans.org

karyotic cells. It has become clear that the LDs-confined deposition and lipolytic degradation of neutral lipids
define longevity in multicellular eukaryotic organisms and yeast. We summarize the evidence in support of
the essential role that LDs play in longevity regulation and propose several molecular mechanisms by which
these dynamic organellar compartments control the aging process in multicellular eukaryotes and yeast.

Introduction and activation of the LDs-associated lipase Tgl4p by CDK

Found in most eukaryotic and some prokaryotic cells,
LDs (lipid droplets) have also been referred to as lipid
bodies, lipid particles, oil bodies and by many other different
names that reflect their cellular and biochemical context in
various biological systems [1,2]. LDs have long been viewed
as relatively inert organellar compartments [3,4]. They were
believed to function only as a site for storing excess energy and
stockpiling fatty acids and sterols in the form of neutral lipids,
mainly triacylglycerols and steryl esters [1,5,6]. Surrounded
by a monolayer of phospholipids and associated proteins,
the neutral lipid core of LDs can be hydrolysed in a regulated
fashion by lipases [7,8]. The resulting retrieval of stored
NEFAs [non-esterified (‘free’) fatty acids], phospholipids and
sterols provides energy via fatty acid oxidation during times
of nutrient scarcity, maintains the homoeostasis of membrane
Biochemical Society Transactions
(cyclin-dependent kinase) 1 controls cell-cycle progression
by mobilizing triacylglycerols, thereby providing fatty acids
and phospholipids for the secretory vesicle-dependent bud
formation and ultimately enabling the G1 /S phase transition
[20]. Furthermore, it appears that LDs in WAT (white adipose
tissue) of mice function as a hub in a regulatory network that,
by modulating the synthesis and secretion of adipokines and
the lipokine C16:1n7-palmitoleate, is central to the multiple
defects in metabolic homoeostasis associated with obesity,
insulin resistance, Type 2 diabetes, atherosclerosis and in-
flammatory disorders [12,14,21–25]. Moreover, by recruiting
certain proteins from other cellular locations, temporally
housing them, managing their availability and modulating
their activities, LDs have been proposed to play important
roles in the regulation of various cellular processes [4,14,18].

lipids during cell growth and division and modulates the
levels of free sterols inside and outside of the cell [1–8].
Novel functions of LDs
An important recent advance in our understanding of the
cell biology of LDs is that they constitute highly dynamic
organellar compartments whose protein and lipid composi-
tion, de novo formation from the ER (endoplasmic reticulum)
template, growth, fragmentation, shrinkage due to lipolysis,
movement and association with other organelles is regulated
by a complex network of protein machines [4–6,8–19]. It has
also become clear that LDs are dynamically integrated into
several vital processes and can serve both as an intracellular
signalling compartment and as an organizing platform
orchestrating these processes. In yeast, the phosphorylation
Key words: aging, anti-aging drug, lipid droplet, longevity, necrosis, peroxisome.
Abbreviations used: C/EBPα, CCAAT/enhancer-binding protein α; CR, calorie restriction; DAF-16,
decay-accelerating factor-16; DAG, diacylglycerol; ER, endoplasmic reticulum; LD, lipid droplet;
NEFA, non–esterified (‘free’) fatty acid; PKC, protein kinase C; SIRT1, sirtuin 1; WAT, white adipose
tissue.
1
These authors contributed equally to this work.
2
To whom correspondence should be addressed (email vtitor@alcor.concordia.ca).
It has been suggested that, by sequestering proteins, LDs
function as an organizing platform that (i) removes excess
proteins from other organellar compartments, inactivates
them and/or stores them for later use; (ii) promotes the
refolding of unfolded proteins targeted to LDs by recruiting
molecular chaperones from the cytosol; (iii) provides a
surface for the ordered degradation of partially unfolded
and misfolded LD-bound proteins that otherwise can form
toxic aggregates in the cytosol; and (iv) delivers some LD-
associated proteins to their target organellar compartments
via permanent or transient contact sites [4,14,18,26–28].
LDs regulate longevity in multicellular
eukaryotic organisms
One of the recently discovered new and unexpected functions
of LDs is the essential role they play in longevity regulation
[21,29–35]. It appears that various interventions that inhibit
the deposition of neutral lipids in LDs or activate their
lipolytic degradation in fat storage tissues of the nematode
Caenorhabditis elegans, the fruitfly Drosophila melanogaster
or laboratory mice also extend the lifespans of these organ-
isms. In fact, at present unknown humoral signals produced


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and secreted by somatic cells in the gonad of C. elegans
promote the nuclear localization of the forkhead transcription
factor DAF-16 (decay-accelerating factor-16) in intestinal
cells, the principal site of neutral lipid storage in this organism
[29]. DAF-16 then induces the expression of a gene encoding
a specific lipase, thereby promoting the lipolysis of neutral
lipids stored in LDs of intestinal cells and extending longevity
by a yet-to-be established mechanism [29]. Furthermore,
the elimination of LD-associated lipases Brummer or ATGL
(adipose triacylglycerol lipase) in the fat body of flies or WAT
of mice respectively shortens lifespan [30,31]. Moreover, by
greatly diminishing the levels of stored neutral lipids in
WAT, both the elimination of WAT-specific insulin receptor
and the replacement of the C/EBPα (CCAAT/enhancer-
binding protein α) protein with its paralogue C/EBPβ extend
longevity in mice [32–34]. Importantly, a low-calorie dietary
regimen known as CR (calorie restriction) extends lifespan
in a wide spectrum of organisms and delays the onset of
age-related diseases in rodent models [21]. The life-extending
effect of CR in worms and flies is mediated by the so-called
sirtuins, a family of NAD+ -dependent protein deacetylases
and ADP ribosylases [21,33]. In mice, CR diet increases the
abundance of the sirtuin SIRT1, which has been shown to
repress transcription of genes that are required for the LD-
confined accumulation of neutral lipids in WAT [21,35]. It has
therefore been proposed that SIRT1 delays aging of CR mice
by shifting the balance between the opposing processes of
LD formation and degradation in WAT towards lipolytic
degradation of neutral lipids in this fat storage tissue
[21,35].
Altogether, these findings imply that the LD-confined
deposition and lipolytic degradation of neutral lipids in fat
storage tissues define longevity of multicellular eukaryotic
organisms. A key challenge for the future will be to
establish the molecular mechanisms by which a delicate
balance between the opposing processes of neutral lipids
accumulation and their lipolytic degradation regulates
longevity in these organisms. Recent studies suggested three
such mechanisms (Figure 1). First, the size of LDs in WAT
of mice modulates the ability of the ER in this tissue to
synthesize and send for secretion various antihyperglycaemic
and pro-hyperglycaemic protein hormones that control
metabolic homoeostasis in other tissues [21,22,36,37]. In the
intestine of worms, LDs that accumulate in this fat storage
tissue contribute sterols for the biosynthesis in the ER and the
subsequent secretion of the lipophilic hormones dafachronic
acid and pregnenolone, both of which delay cellular aging in
other tissues [37]. Thus it is conceivable that the dynamics
of LD-confined deposition and lipolytic degradation of
neutral lipids in fat storage tissues modulates their ability
to synthesize in the ER and then secrete humoral signals
that control longevity-related processes in other tissues (Fig-
ure 1A). Secondly, the lipolysis of LD-deposited neutral lipids
results in the release of the lipokine C16:1n7-palmitoleate, an
unsaturated fatty acid, from WAT of mice [24]. This recently
discovered lipid hormone regulates systemic carbohydrate
and lipid homoeostasis in muscle and liver by promoting
The Dynamic Cell 1051
muscle insulin-sensitivity and attenuating hepatic steatosis
[24]. Hence, the LD-derived C16:1n7-palmitoleate produced
in and then secreted by WAT of mice could function as a
signalling molecule that plays an important role in longevity
regulation (Figure 1B). Thirdly, in response to enhanced
lipolysis of LD-deposited neutral lipids, WAT of mice and
the fat body of flies activate certain regulatory networks that
stimulate mitochondrial biogenesis and fatty acid β-oxidation
in mitochondria [25,34,38]. This, in turn, decreases the levels
of saturated fatty acids secreted by these fat storage tissues,
thereby reducing the risk of lipotoxicity in other tissues
and preventing muscle insulin resistance and hepatic steatosis
[23–25,39]. Importantly, such a stimulation of mitochondrial
biogenesis and fatty acid β-oxidation in WAT of mice
expressing the β-paralogue of C/EBP increases their lifespan
[34]. Therefore it is likely that this third mechanism, which
is confined to fat storage tissues, plays an important role in
delaying cellular aging in peripheral tissues and increasing
longevity of the entire organism (Figure 1C).
LDs play an essential role in longevity
regulation in yeast
Recent findings suggest that LDs play an essential role in
longevity regulation not only in multicellular eukaryotic
organisms but also in yeast [9,40–45]. The budding yeast
Saccharomyces cerevisiae, a genetically and biochemically
manipulatable unicellular eukaryote with annotated genome,
is an advantageous model for understanding the molecular
mechanisms of cellular aging in multicellular eukaryotes
[40]. There are two different ways to monitor yeast aging.
Yeast replicative aging is defined by the maximum number
of daughter cells that a mother cell can produce before
senescence and mimics aging of mitotically active mammalian
cells [41]. By contrast, chronological aging is measured by
the length of time a yeast cell remains viable in a non-dividing
state and mimics aging of postmitotic mammalian cells [42].
Both the replicative and chronological aging of yeast can be
slowed down by CR [40,43], a low-calorie diet that extends
lifespan in various multicellular eukaryotic organisms and
delays the onset or reduces the incidence of many age-related
diseases in rodent models [21]. A CR diet can be imposed in
yeast by reducing the glucose concentration from 2% to 0.5%
in growth medium [40]. Chronologically aging non-CR yeast
grown on 2% glucose (but not CR yeast grown on 0.5% gluc-
ose) accumulate ethanol, a product of glucose fermentation
[40,43]. Importantly, ethanol modulates longevity in chrono-
logically aging yeast by a yet-to-be characterized mechanism
[43]. Of note, ethanol in yeast cells suppresses the synthesis
of certain proteins localized to peroxisomes [44]. Thus it is
tempting to speculate that the accumulation of ethanol in non-
CR yeast represses the synthesis of Fox1p, Fox2p and Fox3p,
all of which are the core enzymes of fatty acid β-oxidation in
peroxisomes [45]. We therefore propose that, because of the
resulting low efficiency of fatty acid oxidation in peroxisomes
of prematurely aging non-CR yeast, they accumulate NEFAs.

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1052 Biochemical Society Transactions (2009) Volume 37, part 5

Figure 1 Possible mechanisms by which the deposition and lipolytic degradation of neutral lipids in LDs of fat storage tissues define
longevity of multicellular eukaryotic organisms
(A) The size of LDs in WAT of mice modulates the ability of the ER in this tissue to synthesize and send for secretion various
pro- and anti-aging adipokines that control longevity-related processes in other tissues. Overloading LDs in WAT with neutral
lipids results in the recruitment of macrophages to this fat storage tissue. Macrophages that infiltrate WAT secrete some of
the pro-aging adipokines, whereas adipocytes of WAT secrete others. In the intestine of worms, LDs that accumulate in this
fat storage tissue contribute sterols for the biosynthesis in the ER and the subsequent secretion of the lipophilic hormones
dafachronic acid and pregnenolone, both of which delay cellular aging in other tissues. (B) The lipolysis of LD-deposited
neutral lipids results in the release of the lipokine C16:1n7-palmitoleate, an unsaturated fatty acid, from WAT of mice. This
LD-derived lipid hormone regulates longevity-related processes in muscle and liver. (C) In response to enhanced lipolysis of
LD-deposited neutral lipids, adipocytes in WAT of mice increase the level of the G-protein α stimulatory subunit (Gs ), whereas
cells in the fat body of flies activate transcription of numerous genes positively regulated by the HNF4 (hepatocyte nuclear
factor 4). This, in turn, stimulates mitochondrial biogenesis and β-oxidation of NEFAs in mitochondria, thereby decreasing the
levels of saturated NEFAs secreted by these fat storage tissues. Saturated NEFAs are lipotoxic in peripheral tissues and cause
muscle insulin resistance and hepatic steatosis. Thus the stimulation of mitochondrial biogenesis and NEFA β-oxidation in fat
storage tissues displaying enhanced lipolysis of neutral lipids plays an important role in delaying cellular aging in peripheral
tissues. Abbreviation: Ac-CoA, acetyl-CoA.


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 The Dynamic Cell 1053

Figure 2 A possible mechanism linking longevity and lipid dynamics in the ER, LDs and peroxisomes of yeast placed on a calorie-rich diet
LDs in yeast cells function as a hub in a regulatory network that modulates neutral lipids synthesis in the ER and fatty acid
oxidation in peroxisomes. The LD–peroxisome association leads to peroxisome invasion into the lipid core of LDs, thereby
generating the so-called pexopodium. Ethanol accumulated in yeast placed on a calorie-rich diet represses the synthesis of
Fox1p, Fox2p and Fox3p, thereby suppressing peroxisomal oxidation of NEFAs (‘FFA’) that originate from triacylglycerols (TAG)
synthesized in the ER and deposited within LDs. The resulting build-up of arrays of NEFAs (gnarls) within LDs of these yeasts
initiates several negative feedback loops regulating the metabolism of TAG. Due to the action of these negative feedback
loops, chronologically aging yeast placed on a calorie-rich diet not only amass TAG in LDs but also accumulate DAG and NEFAs
in the ER. The resulting remodelling of lipid dynamics in these yeasts shortens their lifespan by causing their premature
death due to the following: (i) necrosis triggered by the inability of their peroxisomes to oxidize NEFAs; (ii) lipoapoptosis
initiated in response to the accumulation of DAG and NEFAs; and (iii) a DAG-induced reorganization of the PKC-dependent
signal transduction network affecting multiple stress response- and longevity-related processes. Abbreviation: FFA-CoA, CoA
esters of fatty acids.

It should be emphasized that fatty acid β-oxidation in
yeast peroxisomes is facilitated by their physical association
with LDs. The extensive physical contact existing between
peroxisomes and LDs stimulates the lipolysis of neutral
lipids within LDs, thereby initiating the conversion of newly
formed NEFAs into their CoA esters that then get imported
and oxidized by peroxisomes [9]. The LD–peroxisome
association can lead to peroxisome invasion into the lipid
core of LDs, thereby generating the so-called pexopodia
that exist as individual peroxisomes or as their extensions
penetrating the core of LDs [9]. Importantly, pexopodia of
yeast mutants that were unable to oxidize NEFAs due to the
absence of Fox1p, Fox2p or Fox3p caused the accumulation
of the so-called gnarls within the core of LDs [9]. Gnarls
represent electron-dense arrays of NEFAs accumulated in
excessive amounts within LDs of fox1Δ, fox2Δ and fox3Δ
mutants [9]. In addition, lack of Fox1p, Fox2p or Fox3p
resulted in the build-up of triacylglycerols within the core of
LDs [9]. By extending these observations to lipid dynamics in
LDs and peroxisomes of chronologically aging non-CR yeast,
one could expect that the accumulation of ethanol in non-CR
yeast and the resulting repression of the synthesis of Fox1p,
Fox2p and Fox3p cause the build-up of arrays of NEFAs
(gnarls) and triacylglycerols within the core of their LDs.
Taken together, these findings suggest a mechanism linking
yeast longevity and lipid dynamics in the ER, LDs and
peroxisomes (Figure 2). In this mechanism, LDs in yeast cells
function as a hub in a regulatory network that modulates
neutral lipids synthesis in the ER and fatty acid oxidation
in peroxisomes. We hypothesize that ethanol accumulated in
yeast placed on a calorie-rich diet represses the synthesis of
Fox1p, Fox2p and Fox3p, thereby suppressing peroxisomal
oxidation of NEFAs that originate from triacylglycerols
synthesized in the ER and deposited within LDs. In our


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1054 Biochemical Society Transactions (2009) Volume 37, part 5
hypothesis, the resulting build-up of arrays of NEFAs
(gnarls) within LDs of non-CR yeast initiates several negative
feedback loops regulating the metabolism of triacylglycerols.
Owing to the action of these negative feedback loops, chrono-
logically aging non-CR yeast not only amass triacylglycerols
in LDs but also accumulate DAG (diacylglycerol) and NE-
FAs in the ER (Figure 2). Of note, it has been recently revealed
that (i) loss of peroxisome function triggers necrosis [46,47];
(ii) both NEFAs and DAG induce lipoapoptosis (a caspase-
and mitochondria-independent form of programmed cell
death) [48]; and (iii) the accumulation of DAG triggers a PKC
(protein kinase C)-dependent signal transduction network
affecting multiple stress response- and longevity-related
processes [49,50]. We therefore hypothesize that the proposed
remodelling of lipid dynamics in chronologically aging non-
CR yeast shortens their lifespan by causing their premature
death due to (i) necrosis triggered by the inability of their
peroxisomes to oxidize NEFAs; (ii) lipoapoptosis initiated
in response to the accumulation of DAG and NEFAs; and
(iii) the DAG-induced reorganization of the PKC-dependent
signal transduction network affecting multiple longevity-
related cellular targets (Figure 2).
Recently, we assessed the effect of CR on the dynamics of
age-related changes in the proteomes and lipidomes of ER,
LDs and peroxisomes in chronologically aging yeast. We
also examined how mutations that extend yeast longevity by
impairing lipid metabolism in these organelles influence their
morphologies, abundance, association with each other and
protein and lipid compositions during chronological aging.
Our findings support the proposed model (Figure 2) for a
mechanism in which LDs function as a hub in a regulatory
network that defines the chronological lifespan of yeast
by modulating both neutral lipids synthesis in the ER and
fatty acid oxidation in peroxisomes. By orchestrating several
negative feedback loops that co-ordinate lipid dynamics in a
diet- and genotype-dependent fashion, this network controls
age-related necrotic cell death and multiple stress res-
ponse-related processes. Implementing our understanding of
the mechanism linking longevity and age-related dynamics
of LDs, we developed a lifespan assay that was used for a
high-throughput screening of extensive libraries of small
molecules. We identified five groups of novel anti-aging
drugs that significantly delay yeast aging by remodelling
lipid metabolism in the ER, LDs and peroxisomes and by
activating a distinct set of stress response-related processes
in mitochondria.
Acknowledgments
We are grateful to current and former members of the Titorenko
laboratory for discussions.
Funding
This work was supported by grants from the Canadian Institutes of
Health Research, Natural Sciences and Engineering Research Council

C The Authors Journal compilation 
C 2009 Biochemical Society
of Canada and Concordia University Research Chair Fund. A.A.G. and
T.B.-V. were supported by doctoral scholarships from the Canadian
Institutes of Health Research. V.I.T. is a Canadian Institutes of Health
Research New Investigator and Concordia University Research Chair
in Genomics, Cell Biology and Aging.
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Received 26 March 2009
doi:10.1042/BST0371050

C The Authors Journal compilation 
C 2009 Biochemical Society