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SERIES ON METABOLISMSERIES ON METABOLISM
REVIEW SERIES ON METABOLISM
Tipping the metabolic scales towards increased
longevity in mammals
Celine E. Riera and Andrew Dillin
A hallmark of ageing is dysfunction in nutrient signalling pathways that regulate glucose homeostasis, negatively affecting whole-
body energy metabolism and ultimately increasing the organism’s susceptibility to disease. Maintenance of insulin sensitivity
depends on functional mitochondrial networks, but is compromised by alterations in mitochondrial energy metabolism during
ageing. Here we discuss metabolic paradigms that influence mammalian longevity, and highlight recent advances in identifying
fundamental signalling pathways that influence metabolic health and ageing through mitochondrial perturbations.
Life expectancy has been strikingly prolonged in developed coun-
tries as a positive outcome of medical progress and modern lifestyle.
Nonetheless, with old age comes a wide range of age-associated diseases
including neurodegenerative diseases, cardiovascular and metabolic
disorders, and higher susceptibility to cancer.
Although the clinical manifestations of ageing are well understood,
the genetic or environmental causes driving age-associated decline in
healthspan remain difficult to isolate. By identifying genetic perturba-
tions that can extend lifespan as well as retard the onset of physiological
decline in invertebrate model organisms, ageing research has started
to provide therapeutic strategies to prolong both healthspan and lifes-
pan1. Research over the last decade using the multitude of spatial and
temporal genetic tools available in mice has begun to identify points
of convergence between mammals and invertebrates. In comparison
to humans, mice are relatively short-lived mammals that suffer from
clinically relevant pathologies including metabolic syndrome, osteo-
porosis, cancer, sarcopenia, cardiovascular dysfunction and neurode-
generation2,3. Molecular and cellular pathways have been identified that
not only increase longevity of mammalian model organisms but also
generally promote their healthspan by delaying the onset of metabolic
decline. This delay is tightly coupled to an age-dependent deterio-
ration of insulin metabolism and subsequent disruption of nutrient
uptake by body tissues. Mitochondria play a key role in the utilization
of nutrient substrates for energy production. Alterations in mitochon-
drial biogenesis, dynamics and integrity render an organism unable
to maintain metabolic homeostasis or properly respond to metabolic
demand observed during ageing.
In this Review, we provide an overview of the metabolic signal-
ling pathways that modulate mammalian lifespan and discuss their
potential as therapeutic targets to treat age-associated loss in glucose
homeostasis and healthspan. Finally, we present key mitochondrial
pathways that have been implicated in age-dependent malfunction of
metabolic homeostasis.
Insulin action regulates metabolic health during ageing
The pathologies encountered in mouse longevity studies revealed a
dominant role for glucose homeostasis in regulating metabolic health
during ageing. In humans, ageing is also linked to increased visceral
fat mass, loss in lean mass and a deterioration in insulin sensitivity
resulting in glucose intolerance — all factors that favour the occur-
rence of metabolic syndrome and cardiovascular diseases4,5. Similarly,
in mice, signs of physiological decline are characterized by an increase
in fat mass and the progressive development of glucose intolerance,
reflecting a similar impairment of insulin sensitivity6,7. However, mild
insulin resistance has been observed in a variety of long-lived mice and
is therefore not necessarily an indicator of poor health or shortened
lifespan when paired with improved glucose tolerance7–10. Over the last
decade, elevated energy expenditure has emerged as a putative longev-
ity biomarker, as it has been associated with lifespan extension11. In old
animals, a decrease in energy expenditure is associated with reduced
activity and endurance linked to decreased oxygen consumption and
lipid accumulation in non-adipose tissue. The respiratory exchange
ratio (RER), obtained by indirect calorimetry, compares the volume
of carbon dioxide an organism produces to the volume of oxygen con-
sumed over a given time and varies inversely with lipid oxidation. In
young and healthy mice, the RER displays a youthful circadian shift
from night to day, reflecting the daily transition from carbohydrate
to lipid metabolism. Old mice, however, develop a substrate prefer-
ence towards lipids, losing the capacity to switch between fuel sources
(Fig.1). This is in accordance with a metabolic flexibility theory of
ageing, which predicts that longevity depends on metabolic health,
and lifespan extension is achieved by maintaining a youthful RER, thus
Celine E. Riera and Andrew Dillin are at the Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA
and Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
e-mail: dillin@berkeley.edu
196 NATURE CELL BIOLOGY VOLUME 17 | NUMBER 3 | MARCH 2015
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REVIEW
SERIES ON METABOLISMSERIES ON METABOLISM REVIEW
protecting the organism against systemic damage associated with fat
metabolism and storage. In contrast, the onset of metabolic inflexibility
corresponds to aberrant glucose homeostasis and increased suscepti-
bility to age-onset diseases in response to an age-associated decline
in mitochondrial energy metabolism12. Another mechanism that may
contribute to the deterioration of metabolic health with age operates
through the oscillations of the circadian clock. Modulating the activity
of the major circadian regulators BMAL1 (also known as ARNTL; aryl
hydrocarbon receptor nuclear translocator-like) and CLOCK (clock
circadian regulator) results in premature ageing13, whereas enhanced
transcriptional activity of these factors protects against age-associated
decline in adapting to new circadian periods14. Most physiological,
endocrine and behavioural rhythms are governed by the molecular
clock, and accumulating evidence indicates that disruption of circadian
rhythms is associated with cancer15. Future research is required to shed
light on how the rhythmicity of nutrient homeostatic processes affects
metabolic flexibility and the ageing process.
Genetic manipulation of insulin metabolism in mouse lifespan
and healthspan
To date, dietary restriction is the most robust intervention to increase
healthspan and lifespan in multiple organisms including rodents and
primates, delaying the onset of age-related diseases2,16,17. In mice, dietary
restriction increases insulin sensitivity and induces a healthy transition
of the RER, due to a more dramatic shift from carbohydrate oxidation
and endogenous fatty acid synthesis in the feeding phase to fatty acid
oxidation during resting18. Similarly to dietary restriction, multiple
genetic manipulations in mice improve metabolic flexibility and lon-
gevity. Alterations of components in the insulin and insulin-like growth
factor signalling (IIS) pathway that dampen insulin signalling promote
longevity associated with improved insulin sensitivity. Some of these
long-lived mice include fat-specific insulin receptor knockout (FIRKO)
mice, hypomorphic PI3K mice, and mice overexpressing the liver hor-
mone FGF21 (fibroblast growth factor21), which antagonizes growth
hormone (GH) and insulin-like growth factor 1 (IGF-1)19–21. Reduction
of circulating IGF-1 positively correlates with increased longevity in
inbred mouse strains22, but is also linked to a reduced body size and
even dwarfism23.
Although Ames (Prop1df/Prop1df) and Snell (Pit1dw/Pit1dw) dwarf mice
are extremely long-lived presumably partially because of decreased IIS,
their metabolic characteristics must be interpreted with caution. This
is because profound deficiency in anterior pituitary function results in
other hormonal changes and negatively affects fertility, metabolic fitness,
adiposity, glucose tolerance and insulin secretion, despite considerable
life extension24,25. In humans, hypothyroidism is also characterized by
diminution of the acute insulin response, resulting in impaired glucose
tolerance26, but the effects of this condition on human longevity are
unclear. Thus, the lifespan extension of reduced IIS models must be
uncoupled from their growth delay or hormonal imbalances to isolate
clinically relevant therapeutic targets.
Ageing
Improved glucose homeostasisWild type
Youth:
metabolic health
Old age:
metabolic decline
0.7
1.0
Wild type
Ageing
RER
Decreased energy metabolism
• Insulin resistance
• Glucose intolerance
• Adipose tissue accumulation
Time
Survival (%)
Improved glucose homeostasis
Metabolic diseases
Neurodegenerative diseases
Cancer formation
Metabolic flexibility Metabolic inflexibility
Mitochondrial mass and integrity
0.7
1.0
a
b
c
100
50
0
Figure 1 Metabolic flexibility controls healthspan and lifespan. (a) A
schematic showing survival curves of a wild-type mouse (blue curve)
compared to a long-lived genetic model of improved glucose homeostasis
(green curve). The onset of metabolic decline precedes the appearance of
morbid pathologies associated with insulin resistance and nutrient uptake.
(b) Throughout lifespan, mitochondrial biogenesis, function and dynamics
decline. Accumulation of oversized abnormal mitochondria which result
from impaired degradation of dysfunctional mitochondria is observed after
the onset of metabolic inflexibility. (c) Metabolic flexibility correlates with
a healthy respiratory exchange ratio (RER) resulting from the circadian
shift between carbohydrate (value of 1.0) to lipid metabolism (value of
0.7). Metabolic inflexibility observed at old age correlates with a substrate
preference towards lipids, reflecting an inability to adapt fuel oxidation to
fuel availability.
SERIES ON METABOLISM
NATURE CELL BIOLOGY VOLUME 17 | NUMBER 3 | MARCH 2015 197
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REVIEW SERIES ON METABOLISMSERIES ON METABOLISM
REVIEW
Deletion of TRPV1 (transient receptor potential vanilloid1) pain
receptors in peripheral nerves innervating pancreatic βcells extends
mouse longevity by improving metabolic flexibility and in particu-
lar elevating prandial insulin secretion with age, without the corre-
sponding growth delay or altered body weight observed in decreased
IIS models7. In humans, metabolic syndrome is linked to dementia
and increased incidence of multiple cancers27,28. Strong correlations
between insulin sensitivity and cancer formation have also been found
in the mouse, and reduced cancer incidence is observed in mice with
improved energy expenditure at old age7,29. Mice carrying a TRPV1
mutation have both reduced cancer incidence and delayed onset of
cognitive decline with age. Other genetic manipulations that reduce
IIS meet these criteria to some extent. Long-lived Ames dwarf mice
and GHR-BP (growth-hormone receptor binding protein) knockout
mice display a lower incidence and delayed onset of certain cancers and
tumours, increased insulin sensitivity and improved cognitive func-
tion at old age30–32. Additionally, prolonged rapamycin treatment delays
cancer formation in aged mice and extends lifespan through inhibition
of mTOR (mammalian target of rapamycin), a major cellular nutrient
sensing pathway that regulates cell growth33,34 and integrates insulin
signalling and cell stress signals35. The method by which rapamycin
regulates the rate of ageing is complex, because short-term treatment
results in immunodeficiency and favours glucose intolerance and insu-
lin resistance36,37. However, prolonged treatment results in improved
metabolic profiles, increased oxygen consumption and ketogenesis, and
markedly enhanced insulin sensitivity38. Robust genetic inhibition of
downstream mTOR complex1 (mTORC1) components, including dele-
tion of ribosomal protein S6K1 (S6 kinase1) and enhanced autophagy,
lead to increased longevity with improved glucose tolerance and insulin
sensitivity at mid-age39,40. However, despite the consensus that dampen-
ing mTORC1 activity extends lifespan, several studies report that this
beneficial effect is achieved mostly by slowing cellular growth and can-
cer incidence, without impacting insulin metabolism36,41. These reports
suggest that disruption of the other major mTOR complex, mTORC2,
mediates aspects of the impaired insulin metabolism associated with
rapamycin treatment, in particular the inability to suppress hepatic
gluconeogenesis following insulin release. It is therefore unclear how
prolonged rapamycin exposure promotes metabolic health, despite the
recent report that insulin sensitivity amelioration following rapamycin
treatment might rely on inhibitory effects of both mTOR complexes38.
Better resolution of the mechanism through which rapamycin positively
modulates glucose homeostasis is required to design drugs that can
recapitulate the longevity extension obtained by rapamycin treatment
without its detrimental side effects.
Mitochondria at the core of metabolic flexibility during ageing
Even though cellular energy can be rapidly generated through anaero-
bic glycolysis, it mostly originates from aerobic oxidation of carbohy-
drates and fatty acids in the mitochondria, highlighting this organelle’s
critical role in regulating global metabolic homeostasis. Not only is
insulin secretion from pancreatic βcells mitochondria-dependent, but
insulin signalling also relies on mitochondria to metabolize glucose
in energy-consuming cells. Mitochondrial activity regulates gluconeo-
genesis and triglyceride synthesis in the liver and lipolysis in adipose
tissue, as well as many other vital processes42. Accordingly, mitochon-
drial dysfunction or damage can greatly perturb metabolic flexibility
and insulin sensitivity, impacting metabolic human diseases and age-
ing12,43,44. During the ageing process, mitochondrial biogenesis, func-
tion and dynamics decline (Fig.2)45,46. This is particularly obvious in
skeletal muscle — a highly metabolically active tissue extremely rich in
mitochondria — which undergoes sarcopenia, a critical loss in mito-
chondrial volume density and decline in physical function with age47.
Accumulation of lipids in skeletal muscle, liver and adipose tissue is
indicative of decreased metabolic flexibility with ageing and therefore
demonstrates a global reduction in oxidative phosphorylation capacity
and mitochondrial biogenesis.
Molecular targets that can restore mitochondrial function and meta-
bolic homeostasis at old age have emerged over the past decade. A key
regulator of mitochondrial biogenesis and energy metabolism is the
transcriptional coactivator PGC1α (proliferator-activated receptor γ
coactivatorα)48,49. Decreased PGC1α expression has been implicated
in muscle insulin resistance in humans and diabetic mouse models50,51.
Increasing PGC1α content in mouse skeletal muscle preserves oxida-
tion phosphorylation, preventing muscle wasting and improving meta-
bolic fitness by inhibiting insulin resistance and fat accumulation with
age52. Mechanistically, PGC1α acts by regulating the activity of several
transcription factors — including the nuclear respiratory factors NRF1
and NRF2 and mitochondrial transcription factorA (TFAM) — that
in turn directly or indirectly induce genes related to mitochondrial
biogenesis and respiration53,54. AMP-activated protein kinase (AMPK)-
mediated phosphorylation activates PGC1α in conditions of low cel-
lular energy, which corresponds to a high AMP/ATP ratio, therefore
inhibiting anabolic processes consuming energy and activating cata-
bolic pathways producing energy, such as fatty acid oxidation and
respiration55,56. Strategies to directly manipulate AMPK to improve
mitochondrial function in skeletal muscle have proven successful and
offer important avenues to treat age-associated metabolic decline.
Pharmacological AMPK activation by AICAR (5-Aminoimidazole-
4-carboxamide ribonucleotide) treatment enhances exercise endur-
ance57 and increases mitochondrial biogenesis and respiration in
mouse models of cytochromec oxidase (COX) deficiency, rescuing
the limited exercise capacity of these mice58. Importantly, activat-
ing AMPK by metformin supplementation is also linked to lifespan
extension59, although metformin action on lifespan might depend on
other targets such as mTOR (ref.60). Under low energy conditions,
AMPK also increases the ratio of nicotinamide adenine dinucleotide
NAD+/NADH, a metabolic signal that triggers the NAD-dependent
deacetylase SIRT1 (sirtuin1) and is required for AMPK-dependent
PGC1α activation61. AMPK and SIRT1 can autoregulate each other, a
mechanism that has been postulated to improve the cellular response to
low-energy states62, and that orchestrates a complex catabolic response
that increases mitochondrial biogenesis, enhances antioxidant defence
and improves fatty-acid oxidation.
Mitochondrial oxidative stress and ageing
Mitochondrial networks are vulnerable to oxidative stress, resulting
in impaired cellular function and increasing the chance of cell death.
During ageing, mitochondrial electron transport chain (ETC) efficiency
decreases, reducing ATP generation through increased proton leakage.
Higher metabolic intensities correlated with higher proton conductance
across the inner membrane of skeletal muscle mitochondria were found
in long-lived mice, supporting the ‘uncoupling to survive’ theory11.
198 NATURE CELL BIOLOGY VOLUME 17 | NUMBER 3 | MARCH 2015
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However, proton leakage in the ETC also diminishes the amount of reac-
tive oxygen species (ROS) produced, with ROS being by-products of
mitochondrial ATP generation resulting from oxygen reduction. Thus,
reduction of ROS levels seems to be beneficial by dampening oxida-
tive damage to mitochondria. The recruitment of uncoupling proteins
(UCPs) relieves mitochondrial ROS by uncoupling the proton gradi-
ent. In particular, UCP1, found in metabolically active tissues such as
brown fat, is activated by fatty acids and dissipates the proton gradient
as heat, with a low rate of ATP production allowing fast substrate oxida-
tion and thermogenesis63. The production of superoxide (O2
–) — a toxic
by-product of respiration generated mostly by complexesI and III of the
ETC — may also induce the uncoupling of mitochondria by activating
UCP1 (or other UCPs) under certain conditions requiring fatty acids
and inhibited by purine nucleotides64. Accordingly, increasing energy
expenditure by UCP1 overexpression in mouse muscle has beneficial
effects on metabolic health, extending median but not maximal lifespan,
decreasing adiposity, increasing both core temperature and metabolic
rate, and lowering lymphoma incidence65.
The ‘free radical’ theory of ageing proposes a causative role for
ROS in accumulated cellular damage over time, and in age-associated
pathologies and functional decline of tissues. Supporting this theory,
decreased ROS production from mitochondria has been observed in
response to dietary restriction and linked to improved mitochondrial
function in rodents. Despite the initial claim that increased respiration
following dietary restriction is achieved by higher mitochondrial bio-
genesis66, dietary restriction is now thought to preserve mitochondrial
function by maintaining the integrity of existing cellular components
and increasing the activity of oxidant scavengers such as catalase67.
Mice expressing human catalase in mitochondria are protected from
oxidative damage, cardiac dysfunction and cataract development, and
exhibit extended longevity69. However, a conflicting study reports that
overexpression of human catalase in all tissues is insufficient to extend
lifespan70. PGC1α also minimizes the build-up of ROS through the tran-
scriptional regulation of numerous ROS-detoxifying enzymes68. Other
genetic models challenge the theory that a linear relationship exists
between decreasing ROS and lifespan extension. Increasing mitochon-
drial ROS and oxidative damage do not cause progeria in mice71,72, and
multiple mouse models of increased antioxidant defences also do not
extend lifespan70. Furthermore, mice expressing a defective mitochon-
drial polymerase develop mitochondrial DNA (mtDNA) mutations
↓ β-oxidation
↑ mtDNA mutations
↑ Triglycerides
↑ Fatty Acyl-CoA
↑ Diacylglycerol
↑ ROS
↓ Glucose uptake
Acetyl-CoA
TCA
cycle
↓ ψm
↓ OXPHOS
↑ Stress kinases
PKC, IKK, JNK
IRS-1/2
↑ ROS
↓ Translation mitochondrial proteins
↑ Damaged mitochondrial proteins
P
P
PPP
P
↑ Ser/Thr
phosphorylation IRS-1/2
↓ PI3K
↓ AKT
Insulin receptor
↓ PGC1α
activity
↓ Biogenesis
Mitochondrial stress
↓ NAD+
SIRT1
↓ Dynamics
↑ Aberrant fusion
Nucleus
Mitochondria
Cytoplasm
↓ Mitophagy
↑ Apoptosis
↓ Mitochondrial quality
↓ PGC1α
levels
III III IV
↓ NAD+
NADH
H+
H+
H+
H+
V
ADP↓ ATP
O
2.−
O
2
O
2
O
2.−
a
b
c
d
Figure 2 Effect of ageing on mitochondrial function. Multiple sources of
damage (orange bolts, a–d) cause senescent mitochondrial phenotypes. (a)
Nutrient surplus promotes the accumulation of lipid metabolite intermediates
that overload and hyperpolarize the mitochondria. Incompletely oxidized
lipid products from the tricarboxylic acid cycle (TCA) and reactive oxygen
species (ROS) then build up, which causes oxidative stress to the respiratory
system (OXPHOS; simplified electron transport chain shown for illustrative
purposes). These intermediates also activate stress-sensitive kinases (protein
kinaseC, PKC; c-Jun N-terminal kinase, JNK; and IκB kinase, IKK), which
phosphorylate insulin receptor substrates (IRS-1/2). This disrupts the insulin
signalling pathway, and glucose uptake and glycolysis in response to insulin.
(b) ROS accumulation causes mutations to the mitochondrial DNA (mtDNA)
pool, affecting mitochondrial translation and damage to proteins vital to
OXPHOS and mitochondrial dynamics. (c) Impaired dynamics and decreased
mitophagy with age leads to aberrant mitochondria. (d) Mitochondrial
biogenesis, controlled by PGC1α, declines with age. Insulin resistance
contributes to the development of a vicious cycle of a negative feedback loop
by impairing biogenesis in addition to the TCA cycle and OXPHOS.
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REVIEW
that accelerate ageing by impairing mitochondrial function without
increasing ROS73–75. Although the mtDNA mutator mouse studies ini-
tially challenged the free radical theory of ageing, recent conflicting
evidence suggests that oxidative damage actually occurs in skeletal
muscle of these mice76. Following these controversies, the role of ROS
in ageing is being revisited, mainly supported by evidence obtained
in Caenorhabditiselegans suggesting that high ROS levels may act as
an important signal that triggers a gene expression pattern promoting
survival under stressful conditions77.
Activation of the mitochondrial UPR and longevity
Long-lived mouse models provide supporting evidence for the role of
improving mitochondrial biogenesis and function in forestalling age-
ing. Paradoxically, in C.elegans, lifespan can be increased by reducing
mitochondrial respiration through reduced function of nuclear genes
encoding ETC components78,79. In particular, neuronal knockdown of
COX activates the mitochondrial unfolded protein response (UPRmt), a
mitochondrial proteostasis mechanism that confers increased longevity
to worms80,81. This pathway is part of the mitochondrial quality control
machinery that detects misfolded proteins in the mitochondria, initi-
ating a signalling cascade that leads to the transcription of protective
genes82. Notably, 13 subunits of the oxidative phosphorylation complex
are encoded by mtDNA, whereas the remaining mitochondrial proteins
(of which there are more than 1,000) are encoded by nuclear DNA
and imported into mitochondria to achieve proper folding. The UPRmt
senses imbalances in the stoichiometry of proteins in the mitochon-
drial compartment and relieves the stress by retrograde signalling to
the nucleus through the degradation of misfolded proteins into peptides
by the ClpP1 protease, consequently promoting transcriptional acti-
vation of nuclear-encoded chaperones residing in the mitochondrial
matrix, such as heat shock proteins60 (HSP60) and 70 (HSP70). This
surveillance pathway is conserved in mammalian cells83, but whether
it plays a pro-longevity role in mammals is unknown. In support of its
possible role in mouse lifespan regulation, low expression of a mouse
mitochondrial ribosomal protein (Mrps5) triggers the UPRmt and cor-
relates with increased lifespan of inbred progenies of a cross between
C57BL/6J and DBA/2J mice84.
Evidence from mouse longevity studies suggests that impairing
mitochondrial function can improve lifespan; however, it is unknown
whether the UPRmt is causal for the longevity increase. Constitutive
ablation of SURF1 (surfeit1), a putative assembly factor specific to
COX, results in mild deficiency of COX in mice and significantly
extended mouse longevity85. This is accompanied by a strong deple-
tion of PGC1α levels, mtDNA content, citrate synthase activity and
oxidative-phosphorylation-related genes in these mice, indicative of a
decrease in respiration and mitochondrial biogenesis58. Reduction of
COQ7 (coenzymeQ7, known as Mclk1 in mice), an enzyme responsible
for the biosynthesis of ubiquinone (an ETC component), also extends
mouse lifespan concomitant with ETC dysfunction and decreased
mitochondrial coupling of respiration and ATP synthesis86. Although
these studies confirm that decreased respiration has beneficial effects
on mouse longevity, it is unknown whether the UPRmt following mito-
chondrial dysfunction is required for longevity.
Strikingly, levels of NAD+ were also decreased in the Mclk1+/– mice.
It is well established that NAD+ plays crucial roles in mediating mito-
chondrial energy metabolism by donating electrons to the ETC or by
acting as a coenzyme for rate-limiting citric acid (TCA) cycle enzymes.
Increasing NAD+ levels, by supplementation of a NAD+ precursor or
through a drug such as resveratrol, improves mitochondrial function
by activating SIRT1 in mice, and protects against the metabolic damage
of high-fat feeding87–90. Thus, high NAD+ levels correspond to mito-
chondrial biogenesis and metabolic flexibility, ultimately improving
healthspan. Paradoxically, Mclk1+/– mice are long-lived despite their
depleted NAD+ levels. The mechanisms underlying this lifespan exten-
sion are unclear, and it is plausible that a different longevity paradigm
independent of mitochondrial biogenesis, such as UPRmt, is required
to promote lifespan of these mice. The relationship between UPRmt and
mitochondrial biogenesis is, however, still under debate. Rapamycin
and resveratrol treatment, which extend lifespan and metabolic fit-
ness, increased respiration in mammalian cells and induced the UPRmt
(ref.84). Thus, it is unclear whether UPRmt in mammals predicts longev-
ity and can be triggered as a cell survival mechanism following severe
mitochondrial impairment, or as a response to mitonuclear imbalance
that facilitates biogenesis. More investigation is necessary to elucidate
the physiological implication of the UPRmt in mammalian ageing.
Insulin resistance, mitochondrial perturbations and dynamics
Mitochondrial dysfunction has been implicated strongly in the onset
of metabolic diseases. Cells cope with nutrient supply by increasing
mitochondrial content, but persistent nutrient surplus can overload
the mitochondria and cause dysfunction, a phenomenon also observed
with ageing, as mitochondrial capacity declines (Fig.2). This functional
decline coincides with a global reduction in oxidative capacity of the
skeletal muscle of patients with type2 diabetes91, and contributes to
insulin resistance51. Energy excess overloads and hyperpolarizes mito-
chondria, leading to the accumulation of fatty-acyl-CoA and diacyl-
glycerol, causing excessive production of ROS. These mitochondrial
metabolites activate stress-sensing-kinases such as c-Jun N-terminal
kinase and protein kinaseC in the cytoplasm (which phosphorylate
insulin receptor substrates), impairing insulin signalling in glucose-
consuming tissues such as skeletal muscle and liver92,93. Insulin-
stimulated glucose transport is inhibited in these tissues and reduces
peripheral energy metabolism.
Furthermore, decreased brain insulin signalling is also observed
in ageing and contributes to neurodegenerative disorders, as a conse-
quence of insulin resistance and decreased insulin transport through
the blood–brain barrier94. Abnormal insulin metabolism in the brain
might originate from mitochondrial dysfunction, as the brain is highly
vulnerable to oxidative stress and elevated ROS levels can aggravate
insulin resistance95,96. Similar observations were made in the hypothala-
mus and hippocampus of mice fed a high-fat diet97,98. Downregulation
of the mitochondrial chaperone protein HSP60 by excessive adipokine
stimuli plays a central role in the onset of oxidative stress leading to
mitochondrial dysfunction and hypothalamic insulin resistance99.
Whether chaperone levels are also regulated by age-associated stress
in the brain and confer mitochondrial dysfunction and deficits in brain
energy metabolism remains undetermined.
Mitochondrial architecture is tightly regulated by the dynamic
opposing processes of fusion and fission. Mitochondrial dynam-
ics reflect bioenergetic adaptation to metabolic demand, facilitating
mixing and exchange of mitochondrial contents such as mtDNA or
metabolites100. Mitochondrial morphology and density are modulated
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by variations in nutrient availability, with starvation triggering a fused
state that facilitates autophagy101. These changes in mitochondrial
architecture can affect oxidative phosphorylation complex assembly
and ATP synthesis, allowing mitochondria to reorganize and dispose
of damaged elements through mitophagy, an autophagic process that
eliminates damaged mitochondria102. Mitophagy prevents cell apop-
tosis or necrosis following excessive ROS accumulation, pro-inflam-
matory signals or permeabilization of mitochondrial membranes, but
the efficiency of autophagy declines with age103. Fission allows the
segregation of damaged mitochondria and their recycling through
autophagic processes, thereby ensuring mitochondria turnover and
cellular viability, whereas fusion counterbalances functional defects
and allows genetic complementation. Oversized abnormal mito-
chondria are present in senescent cells, as a result of dysfunctional
mitochondrial degradation104. Youthful mitochondrial fragmentation
can be restored in senescent cells by depleting critical mediators of
fusion, the dynamin-related proteins FIS1 (fission1 (mitochondrial
outer membrane) homolog) and OPA1 (optic atrophy1). Recently,
lack of the pro-fusion mitofusins Mfn1 and Mfn2 has been implicated
in regulation of whole-body energy homeostasis in distinct popula-
tions of hypothalamic neurons in mice105–107. Mfn2 deficiency pre-
vents changes in mitochondrial dynamics and communication with
the endoplasmic reticulum (ER), causing ER stress, insulin resistance
in skeletal muscle and liver tissues, and hypothalamic leptin resist-
ance, thus promoting obesity105–109. Mitochondrial health relies on a
tight contact with the ER that provides critical resources to the mito-
chondria such as mitochondrial lipids and calcium ions, which are
involved in mitochondrial dynamics and regulation of the TCA cycle.
Although gradual impairment of mitochondrial dynamics with age is
a proposed hypothesis for age-associated mitochondrial dysfunction,
additional layers of regulation may exist, including ER-mitochondria
tethering and impaired insulin signalling due to ER stress, resulting in
cell-autonomous inflammation (as observed in type2 diabetes)110,111.
One of the main pro-inflammatory transcriptional programs induced
following ER stress is the NF-κB (nuclear factorκB) signalling path-
way112. Interestingly, restoring hypothalamic immunity upon ageing
through the blockade of NF-κB signalling in microglia is sufficient to
extend lifespan in mice113. It will be critical to define whether meta-
bolic decline during ageing is mediated by the disruption of intricate
connections between mitochondria and the ER, and the onset of ER
stress and inflammation.
Conclusions and future perspectives
In light of the evidence reviewed here, progressive mitochondrial dys-
function is implicated in the deterioration of insulin sensitivity during
normal ageing, consequently impairing insulin signalling in central
and peripheral tissues, and contributing to a loss of metabolic flex-
ibility. Thus, restoring mitochondrial biogenesis is likely to provide
a therapeutic avenue to rejuvenate metabolism. However, in conflict-
ing studies, reduced respiration and biogenesis throughout life can
also increase lifespan, indicating an additional level of complexity.
Epigenetic regulation is now emerging as a potent factor influencing
mitochondrial biogenesis or integrity following the lack of exercise and
overfeeding. Notably, DNA hypermethylation suppresses the expres-
sion of Pgc1α and Tfam in mice, and microRNAs have the ability to
silence gene expression of Ucp2 and Mfn2, thus negatively affecting
biogenesis, oxidative phosphorylation and mitochondrial dynamics114.
Whether such epigenetic signatures are characteristic of the ageing
process remains poorly understood; thus, it will be essential to assess
the chain of events that leads to impaired transcriptional networks
that maintain biogenesis (nuclear and mitochondrial transcription) as
well as mitochondrial quality control machinery (dynamics, mitophagy
and the UPRmt). In particular, we are beginning to envision that these
processes are likely to co-regulate each other, as highlighted by the
reliance on fusion and fission events in order to remove damaged mito-
chondria through mitophagy and the dependence of biogenesis on
protein translocation resulting from mitochondrial dynamics. These
preliminary discoveries are identifying novel therapeutic perspectives
in the effort to delay the onset of metabolic decline and age-associated
metabolic diseases.
ACKNOWLEDGMENTS
We apologize to our colleagues for omitting numerous references due to space
limitations. We thank Carsten Merkwirth and Kristen Berendzen for their helpful
comments on the manuscript. C.E.R is supported by the American Diabetes
Association Pathway to Stop Diabetes Grant 1-15-INI-12.
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
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