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Tipping the metabolic scales towards increased longevity in mammals


Abstract and Figures

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.
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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.
© 2015 Macmillan Publishers Limited. All rights reserved
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 factor21), 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.
Improved glucose homeostasisWild type
metabolic health
Old age:
metabolic decline
Wild type
Decreased energy metabolism
• Insulin resistance
• Glucose intolerance
• Adipose tissue accumulation
Survival (%)
Improved glucose homeostasis
Metabolic diseases
Neurodegenerative diseases
Cancer formation
Metabolic flexibility Metabolic inflexibility
Mitochondrial mass and integrity
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.
© 2015 Macmillan Publishers Limited. All rights reserved
Deletion of TRPV1 (transient receptor potential vanilloid1) pain
receptors in peripheral nerves innervating pancreatic βcells 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 age3032. 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 complex1 (mTORC1) components, including dele-
tion of ribosomal protein S6K1 (S6 kinase1) 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 organelles
critical role in regulating global metabolic homeostasis. Not only is
insulin secretion from pancreatic βcells 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
coactivatorα)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 factorA (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 cytochromec 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 (sirtuin1) 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.
© 2015 Macmillan Publishers Limited. All rights reserved
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 complexesI 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
mtDNA mutations
Fatty Acyl-CoA
Glucose uptake
Stress kinases
Translation mitochondrial proteins
Damaged mitochondrial proteins
phosphorylation IRS-1/2
Insulin receptor
Mitochondrial stress
Aberrant fusion
Mitochondrial quality
Figure 2 Effect of ageing on mitochondrial function. Multiple sources of
damage (orange bolts, ad) 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
kinaseC, 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.
© 2015 Macmillan Publishers Limited. All rights reserved
that accelerate ageing by impairing mitochondrial function without
increasing ROS7375. 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 Caenorhabditiselegans 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 proteins60 (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 (surfeit1), 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 (coenzymeQ7, 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 feeding8790. 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 type2 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 kinaseC 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
© 2015 Macmillan Publishers Limited. All rights reserved
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 (fission1 (mitochondrial
outer membrane) homolog) and OPA1 (optic atrophy1). 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 type2 diabetes)110,111.
One of the main pro-inflammatory transcriptional programs induced
following ER stress is the NFB (nuclear factorκB) 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.
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.
The authors declare no competing financial interests.
1. López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks
of aging. Cell 153, 1194–1217 (2013).
2. De Cabo, R., Carmona-Gutierrez, D., Bernier, M., Hall, M.N. & Madeo, F. The search for
antiaging interventions: from elixirs to fasting regimens. Cell 157, 1515–1526 (2014).
3. Selman, C. & Withers, D.J. Mammalian models of extended healthy lifespan. Philos.
Trans. R.Soc. Lond. Ser.B.Biol. Sci. 366, 99–107 (2011).
4. Rowe, J.W., Minaker, K.L., Pallotta, J.A. & Flier, J.S. Characterization of the insulin
resistance of aging. J.Clin. Invest. 71, 1581–1587 (1983).
5. Fink, R.I., Kolterman, O. G., Griffin, J. & Olefsky, J. M. Mechanisms of insulin
resistance in aging. J.Clin. Invest. 71, 1523–1535 (1983).
6. Houtkooper, R.H. etal. The metabolic footprint of aging in mice. Sci. Rep. 1, 134
7. Riera, C. E. et al. TRPV1 pain receptors regulate longevity and metabolism by
neuropeptide signaling. Cell 157, 1023–1036 (2014).
8. Kurosu, H. etal. Suppression of aging in mice by the hormone klotho. Science 309,
1829–1833 (2005).
9. Selman, C. etal. Evidence for lifespan extension and delayed age-related biomarkers
in insulin receptor substrate1 null mice. FASEB J. 22, 807–818 (2008).
10. Taguchi, A., Wartschow, L.M. & White, M.F. Brain IRS2 signaling coordinates life span
and nutrient homeostasis. Science 317, 369–372 (2007).
11. Speakman, J.R. etal. Uncoupled and surviving: individual mice with high metabolism
have greater mitochondrial uncoupling and live longer. Aging Cell 3, 87–95 (2004).
12. Galgani, J.E., Moro, C. & Ravussin, E. Metabolic flexibility and insulin resistance. Am.
J.Physiol. Endocrinol. Metab. 295, 1009–1017 (2008).
13. Kondratov, R.V., Kondratova, A.A., Gorbacheva, V.Y., Vykhovanets, O.V. & Antoch,
M.P. Early aging and age-related pathologies in mice deficient in BMAL1, the core
component of the circadian clock. Genes Dev. 20, 1868–1873 (2006).
14. Chang, H-C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a
mechanism that decays with aging. Cell 153, 1448–1460 (2013).
15. Sahar, S. & Sassone-Corsi, P. Metabolism and cancer: the circadian clock connection.
Nat. Rev. Cancer 9, 886–896 (2009).
16. Fontana, L., Partridge, L. & Longo, V.D. Dietary restriction, growth factors and aging:
from yeast to humans. Science 328, 321–326 (2010).
17. Mair, W. & Dillin, A. Aging and survival: the genetics of life span extension by dietary
restriction. Annu. Rev. Biochem. 77, 727–754 (2008).
18. Bruss, M.D., Khambatta, C.F., Ruby, M.A., Aggarwal, I. & Hellerstein, M.K. Calorie
restriction increases fatty acid synthesis and whole body fat oxidation rates. Am.
J.Physiol. Endocrinol. Metab. 298, E108–E116 (2010).
19. Bluher, M. Extended longevity in mice lacking the insulin receptor in adipose tissue.
Science 299, 572–574 (2003).
20. Foukas, L.C. etal. Long-term p110? PI3K inactivation exerts a beneficial effect on
metabolism. EMBO Mol. Med. 5, 563–571 (2013).
21. Zhang, Y. etal. The starvation hormone, fibroblast growth factor-21, extends lifespan
in mice. eLife 1, e00065 (2012).
22. Yuan, R. etal. Aging in inbred strains of mice: study design and interim report on
median lifespans and circulating IGF1 levels. Aging Cell 8, 277–287 (2009).
23. Berryman, D.E., Christiansen, J.S., Johannsson, G., Thorner, M.O. & Kopchick, J.J.
Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models.
Growth Horm. IGF Res. 18, 455–471 (2008).
24. Hsieh, C-C., DeFord, J. H., Flurkey, K., Harrison, D. E. & Papaconstantinou, J.
Implications for the insulin signaling pathway in Snell dwarf mouse longevity: a similarity
with the C.elegans longevity paradigm. Mech. Ageing Dev. 123, 1229–1244 (2002).
© 2015 Macmillan Publishers Limited. All rights reserved
25. Dominici, F.P., Hauck, S., Argentino, D.P., Bartke, A. & Turyn, D. Increased insulin
sensitivity and upregulation of insulin receptor, insulin receptor substrate (IRS)-1 and
IRS-2 in liver of Ames dwarf mice. J.Endocrinol. 173, 81–94 (2002).
26. Shah, J.H. & Cerchio, G.M. Hypoinsulinemia of hypothyroidism. Arch. Intern. Med.
132, 657–661 (1973).
27. Tsugane, S. & Inoue, M. Insulin resistance and cancer: epidemiological evidence.
Cancer Sci. 101, 1073–1079 (2010).
28. Naderali, E.K., Ratcliffe, S.H. & Dale, M.C. Obesity and Alzheimer’s disease: a link
between body weight and cognitive function in old age. Am. J.Alzheimers Dis. Other
Demen. 24, 445–449 (2009).
29. Ortega-Molina, A. et al. Pten positively regulates brown adipose function, energy
expenditure, and longevity. Cell Metab. 15, 382–394 (2012).
30. Coschigano, K. T., Clemmons, D., Bellush, L.L. & Kopchick, J. J. Assessment of
growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141,
2608–2613 (2000).
31. Ikeno, Y., Bronson, R.T., Hubbard, G.B., Lee, S. & Bartke, A. Delayed occurrence
of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity.
J.Gerontol. A.Biol. Sci. Med. Sci. 58, 291–296 (2003).
32. Ikeno, Y. etal. Reduced incidence and delayed occurrence of fatal neoplastic diseases
in growth hormone receptor/binding protein knockout mice. J.Gerontol. A.Biol. Sci.
Med. Sci. 64, 522–529 (2009).
33. Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically
heterogeneous mice. Nature 460, 392–395 (2009).
34. Miller, R.A. etal. Rapamycin, but not resveratrol or simvastatin, extends life span of
genetically heterogeneous mice. J.Gerontol. A.Biol. Sci. Med. Sci. 66A, 191–201
35. Corradetti, M.N. & Guan, K-L. Upstream of the mammalian target of rapamycin: do
all roads pass through mTOR? Oncogene 25, 6347–6360 (2006).
36. Lamming, D.W. etal. Rapamycin-induced insulin resistance is mediated by mTORC2
loss and uncoupled from longevity. Science 335, 1638–1643 (2012).
37. Roy, J., Paquette, J-S., Fortin, J.-F. & Tremblay, M.J. The immunosuppressant
rapamycin represses human immunodeficiency virus type1 replication. Antimicrob.
Agents Chemother. 46, 3447–3455 (2002).
38. Fang, Y. etal. Duration of rapamycin treatment has differential effects on metabolism
in mice. Cell Metab. 17, 456–462 (2013).
39. Pyo, J-O. etal. Overexpression of Atg5 in mice activates autophagy and extends
lifespan. Nat. Commun. 4, 2300 (2013).
40. Selman, C. etal. Ribosomal protein S6 kinase1 signaling regulates mammalian life
span. Science 326, 140–144 (2009).
41. Wu, J. J. et al. Increased mammalian lifespan and a segmental and tissue-specific
slowing of aging after genetic reduction of mTOR expression. Cell Rep. 4, 913–920
42. Saltiel, A.R. & Kahn, C.R. Insulin signalling and the regulation of glucose and lipid
metabolism. Nature 414, 799–806 (2001).
43. Bratic, A. & Larsson, N-G. The role of mitochondria in aging. J.Clin. Invest. 123,
951–957 (2013).
44. Schapira, A.H.V. Mitochondrial diseases. Lancet 379, 1825–1834 (2012).
45. Herbener, G.H. A morphometric study of age-dependent changes in mitochondrial
population of mouse liver and heart. J.Gerontol. 31, 8–12 (1976).
46. Lanza, I.R. & Nair, K.S. Mitochondrial function as a determinant of life span. Pflüg.
Arch. Eur. J.Physiol. 459, 277–289 (2010).
47. Conley, K.E., Jubrias, S.A. & Esselman, P.C. Oxidative capacity and ageing in human
muscle. J.Physiol. 526, 203–210 (2000).
48. Lin, J. etal. Transcriptional co-activator PGC-1α drives the formation of slow-twitch
muscle fibres. Nature 418, 797–801 (2002).
49. Puigserver, P. etal. A cold-inducible coactivator of nuclear receptors linked to adaptive
thermogenesis. Cell 92, 829–839 (1998).
50. Mootha, V.K. etal. PGC-1α-responsive genes involved in oxidative phosphorylation
are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).
51. Patti, M.E. etal. Coordinated reduction of genes of oxidative metabolism in humans
with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc. Natl Acad.
Sci. USA 100, 8466–8471 (2003).
52. Wenz, T., Rossi, S.G., Rotundo, R.L., Spiegelman, B.M. & Moraes, C.T. Increased
muscle PGC-1α expression protects from sarcopenia and metabolic disease during
aging. Proc. Natl Acad. Sci. USA 106, 20405–20410 (2009).
53. Anderson, R. & Prolla, T. PGC-1α in aging and anti-aging interventions. Biochim.
Biophys. Acta 1790, 1059–1066 (2009).
54. Austin, S. & St-Pierre, J. PGC1α and mitochondrial metabolism — emerging concepts
and relevance in ageing and neurodegenerative disorders. J.Cell Sci. 125, 4963–4971
55. Cantó, C. etal. AMPK regulates energy expenditure by modulating NAD+ metabolism
and SIRT1 activity. Nature 458, 1056–1060 (2009).
56. Jäger, S., Handschin, C., St-Pierre, J. & Spiegelman, B.M. AMP-activated protein
kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc.
Natl Acad. Sci. USA 104, 12017–12022 (2007).
57. Narkar, V.A. et al. AMPK and PPARδ agonists are exercise mimetics. Cell 134,
405–415 (2008).
58. Viscomi, C. etal. Invivo correction of COX deficiency by activation of the AMPK/PGC-1α
axis. Cell Metab. 14, 80–90 (2011).
59. Martin-Montalvo, A. etal. Metformin improves healthspan and lifespan in mice. Nat.
Commun. 4, 2192 (2013).
60. Kalender, A. etal. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-
dependent manner. Cell Metab. 11, 390–401 (2010).
61. Cantó, C. etal. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting
and exercise in skeletal muscle. Cell Metab. 11, 213–219 (2010).
62. Price, N.L. etal. SIRT1 is required for AMPK activation and the beneficial effects of
resveratrol on mitochondrial function. Cell Metab. 15, 675–690 (2012).
63. Nicholls, D.G., Bernson, V.S.M. & Heaton, G.M. in Effectors of Thermogenesis (eds.
Girardier, L. & Seydoux, J.) 89–93 (Birkhäuser Basel, 1978).
64. Echtay, K.S. etal. Superoxide activates mitochondrial uncoupling proteins. Nature
415, 96–99 (2002).
65. Gates, A. C. et al. Respiratory uncoupling in skeletal muscle delays death and
diminishes age-related disease. Cell Metab. 6, 497–505 (2007).
66. Nisoli, E. etal. Calorie restriction promotes mitochondrial biogenesis by inducing the
expression of eNOS. Science 310, 314–317 (2005).
67. Lanza, I.R. etal. Chronic caloric restriction preserves mitochondrial function in senescence
without increasing mitochondrial biogenesis. Cell Metab. 16, 777–788 (2012).
68. St-Pierre, J. etal. Bioenergetic analysis of peroxisome proliferator-activated receptorγ
coactivators 1α and 1β (PGC-1α and PGC-1β) in muscle cells. J.Biol. Chem. 278,
26597–26603 (2003).
69. Schriner, S.E. etal. Extension of murine life span by overexpression of catalase targeted
to mitochondria. Science 308, 1909–1911 (2005).
70. Pérez, V.I. etal. The overexpression of major antioxidant enzymes does not extend the
lifespan of mice. Aging Cell 8, 73–75 (2009).
71. Van Remmen, H. etal. Life-long reduction in MnSOD activity results in increased
DNA damage and higher incidence of cancer but does not accelerate aging. Physiol.
Genomics 16, 29–37 (2003).
72. Zhang, Y. etal. Mice deficient in both Mn superoxide dismutase and glutathione
peroxidase-1 have increased oxidative damage and a greater incidence of pathology
but no reduction in longevity. J.Gerontol.A.Biol. Sci. Med. Sci. 64, 1212–1220
73. Edgar, D. etal. Random point mutations with major effects on protein-coding genes
are the driving force behind premature aging in mtDNA mutator mice. Cell Metab. 10,
131–138 (2009).
74. Trifunovic, A. etal. Premature ageing in mice expressing defective mitochondrial DNA
polymerase. Nature 429, 417–423 (2004).
75. Vermulst, M. etal. DNA deletions and clonal mutations drive premature aging in
mitochondrial mutator mice. Nat. Genet. 40, 392–394 (2008).
76. Kolesar, J.E. etal. Defects in mitochondrial DNA replication and oxidative damage in
muscle of mtDNA mutator mice. Free Radic. Biol. Med. 75, 241–251 (2014).
77. Yee, C., Yang, W. & Hekimi, S. The intrinsic apoptosis pathway mediates the
pro-longevity response to mitochondrial ROS in C.elegans. Cell 157, 897–909 (2014).
78. Dillin, A. etal. Rates of behavior and aging specified by mitochondrial function during
development. Science 298, 2398–2401 (2002).
79. Lee, S.S. etal. A systematic RNAi screen identifies a critical role for mitochondria in
C.elegans longevity. Nat. Genet. 33, 40–48 (2003).
80. Durieux, J., Wolff, S. & Dillin, A. The cell-non-autonomous nature of electron transport
chain-mediated longevity. Cell 144, 79–91 (2011).
81. Yoneda, T. etal. Compartment-specific perturbation of protein handling activates genes
encoding mitochondrial chaperones. J.Cell Sci. 117, 4055–4066 (2004).
82. Mottis, A., Jovaisaite, V. & Auwerx, J. The mitochondrial unfolded protein response in
mammalian physiology. Mamm. Genome 25, 424–433 (2014).
83. Zhao, Q. etal. A mitochondrial specific stress response in mammalian cells. EMBO J.
21, 4411–4419 (2002).
84. Houtkooper, R.H. et al. Mitonuclear protein imbalance as a conserved longevity
mechanism. Nature 497, 451–457 (2013).
85. Dell’agnello, C. etal. Increased longevity and refractoriness to Ca2+-dependent
neurodegeneration in Surf1 knockout mice. Hum. Mol. Genet. 16, 431–444
86. Lapointe, J. & Hekimi, S. Early mitochondrial dysfunction in long-lived Mclk1+/– mice.
J.Biol. Chem. 283, 26217–26227 (2008).
87. Bai, P. etal. PARP-2 regulates SIRT1 expression and whole-body energy expenditure.
Cell Metab. 13, 450–460 (2011).
88. Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1
activation. Cell Metab. 13, 461–468 (2011).
89. Lagouge, M. etal. Resveratrol improves mitochondrial function and protects against
metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).
90. Yoshino, J., Mills, K.F., Yoon, M.J. & Imai, S. Nicotinamide mononucleotide, a key
NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in
mice. Cell Metab. 14, 528–536 (2011).
91. Kelley, D.E., He, J., Menshikova, E.V. & Ritov, V.B. Dysfunction of mitochondria in
human skeletal muscle in type2 diabetes. Diabetes 51, 2944–2950 (2002).
92. Fisher-Wellman, K.H. & Neufer, P.D. Linking mitochondrial bioenergetics to insulin
resistance via redox biology. Trends Endocrinol. Metab. 23, 142–153 (2012).
93. Lowell, B.B. & Shulman, G.I. Mitochondrial dysfunction and type2 diabetes. Science
307, 384–387 (2005).
94. Cholerton, B., Baker, L.D. & Craft, S. Insulin resistance and pathological brain ageing.
Diabet. Med. 28, 1463–1475 (2011).
95. Evans, J.L., Maddux, B.A. & Goldfine, I.D. The molecular basis for oxidative stress-
induced insulin resistance. Antioxid. Redox Signal. 7, 1040–1052 (2005).
96. Halliwell, B. Reactive oxygen species and the central nervous system. J.Neurochem.
59, 1609–1623 (1992).
97. Pipatpiboon, N., Pratchayasakul, W., Chattipakorn, N. & Chattipakorn, S.C. PPARγ
agonist improves neuronal insulin receptor function in hippocampus and brain
mitochondria function in rats with insulin resistance induced by long term high-fat
diets. Endocrinology 153, 329–338 (2012).
© 2015 Macmillan Publishers Limited. All rights reserved
98. Thaler, J.P. etal. Obesity is associated with hypothalamic injury in rodents and humans.
J.Clin. Invest. 122, 153–162 (2012).
99. Kleinridders, A. et al. Leptin regulation of Hsp60 impacts hypothalamic insulin
signaling. J.Clin. Invest. 123, 4667–4680 (2013).
100. Chan, D.C. Fusion and fission: interlinked processes critical for mitochondrial health.
Annu. Rev. Genet. 46, 265–287 (2012).
101. Gomes, L.C., Di Benedetto, G. & Scorrano, L. During autophagy mitochondria
elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13,
589–598 (2011).
102. Green, D.R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-
inflammation-cell death axis in organismal aging. Science 333, 1109–1112
103. Zhang, J. Autophagy and mitophagy in cellular damage control. Redox Biol. 1, 19–23
104. Lee, S. etal. Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate
cellular senescence. J.Biol. Chem. 282, 22977–22983 (2007).
105. Dietrich, M.O., Liu, Z-W. & Horvath, T.L. Mitochondrial dynamics controlled by
mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155,
188–199 (2013).
106. Schneeberger, M. etal. Mitofusin2 in POMC neurons connects ER stress with leptin
resistance and energy imbalance. Cell 155, 172–187 (2013).
107. De Brito, O. M. & Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to
mitochondria. Nature 456, 605–610 (2008).
108. Sebastián, D. etal. Mitofusin2 (Mfn2) links mitochondrial and endoplasmic reticulum
function with insulin signaling and is essential for normal glucose homeostasis. Proc.
Natl Acad. Sci. USA 109, 5523–5528 (2012).
109. Muñoz, J.P. etal. Mfn2 modulates the UPR and mitochondrial function via repression
of PERK. EMBO J. 32, 2348–2361 (2013).
110. Ozcan, U. etal. Endoplasmic reticulum stress links obesity, insulin action, and type2
diabetes. Science 306, 457–461 (2004).
111. Garg, A.D. etal. ER stress-induced inflammation: does it aid or impede disease
progression? Trends Mol. Med. 18, 589–598 (2012).
112. Zhang, K. & Kaufman, R.J. From endoplasmic-reticulum stress to the inflammatory
response. Nature 454, 455–462 (2008).
113. Zhang, G. etal. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB
and GnRH. Nature 497, 211–216 (2013).
114. Cheng, Z. & Almeida, F.A. Mitochondrial alteration in type2 diabetes and obesity:
an epigenetic link. Cell Cycle 13, 890–897 (2014).
© 2015 Macmillan Publishers Limited. All rights reserved
... Previous studies have revealed that preservation of mitochondrial function is a key player in maintaining the integrity of many organ systems [9]. In addition, mitochondrial dysfunction, together with perturbation to metabolic flexibility [10], result in a decrease in oxygen consumption and lower ATP production; these have been observed in older subjects who have low physical performance [11] and are a mortality risk factor [12]. Furthermore, mitochondrial dysfunction during aging alters mitochondrial energy metabolism, which, in turn, disturbs the nutrient sensing pathways that regulate glucose homeostasis and insulin sensitivity. ...
... Furthermore, mitochondrial dysfunction during aging alters mitochondrial energy metabolism, which, in turn, disturbs the nutrient sensing pathways that regulate glucose homeostasis and insulin sensitivity. These impaired cellular responses compromise whole body energy metabolism and ultimately increase the risks of age-related disease [10]. ...
... Previous studies have revealed that preservation of mitochondrial function is a key player in maintaining the integrity of many organ systems [9]. In addition, mitochondrial dysfunction, together with perturbation to metabolic flexibility [10], result in a decrease in oxygen consumption and lower ATP production; these have been observed in older subjects who have low physical performance [11] and are a mortality risk factor [12]. Furthermore, mitochondrial dysfunction during aging alters mitochondrial energy metabolism, which, in turn, disturbs the nutrient sensing pathways that regulate glucose homeostasis and insulin sensitivity. ...
... Furthermore, mitochondrial dysfunction during aging alters mitochondrial energy metabolism, which, in turn, disturbs the nutrient sensing pathways that regulate glucose homeostasis and insulin sensitivity. These impaired cellular responses compromise whole body energy metabolism and ultimately increase the risks of age-related disease [10]. ...
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Background The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. Methods Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging. Results Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age. Conclusions Our findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2.
... Cellular organelles mitochondria were likely originated from bacteria; indeed, they share a number of metabolic pathways 71 . Mitochondria are involved in aging processes, as a signaling hub for both metabolism and the vital signaling pathways 72 . Our results demonstrated that Probio-M9 enhanced intestinal tract UPR mt levels and extended lifespan of worms, probably through the mitochondrial ETC components ISP-1 and NUO-6. ...
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Probiotics have been characterized as useful for maintaining the balance of host gut flora and conferring health effects, but few studies have focused on their potential for delaying aging in the host. Here we show that Lacticaseibacillus rhamnosus Probio-M9 (Probio-M9), a healthy breast milk probiotic, enhances the locomotor ability and slows the decline in muscle function of the model organism Caenorhabditis elegans. Live Probio-M9 significantly extends the lifespan of C. elegans in a dietary restriction-independent manner. By screening various aging-related mutants of C. elegans, we find that Probio-M9 extends lifespan via p38 cascade and daf-2 signaling pathways, independent on daf-16 but dependent on skn-1. Probio-M9 protects and repairs damaged mitochondria by activating mitochondrial unfolded protein response. The significant increase of amino acids, sphingolipid, galactose and fatty acids in bacterial metabolites might be involved in extending the lifespan of C. elegans. We reveal that Probio-M9 as a dietary supplementation had the potential to delay aging in C. elegans and also provide new methods and insights for further analyzing probiotics in improving host health and delaying the occurrence of age-related chronic diseases. Lacticaseibacillus rhamnosus Probio-M9 extends the lifespan of C. elegans independent of dietary restriction via p38 cascade and daf-2 signaling pathways, revealing its potential to delay aging in C. elegans.
... In addition, reduced ATP synthesis increased ROS production and led to lowered redox defenses. However, it is unclear to what extent these processes are natural causes or consequences of the aging process [57,58]. The relationship between mitochondria and the aging process has been described in several studies over the years. ...
Full-text available
The study of aging is an important topic in contemporary research. Considering the demographic changes and the resulting shifts towards an older population, it is of great interest to preserve youthful physiology in old age. For this endeavor, it is necessary to choose an appropriate model. One such model is the nematode Caenorhabditis elegans (C. elegans), which has a long tradition in aging research. In this review article, we explore the advantages of using the nematode model in aging research, focusing on bioenergetics and the study of secondary plant metabolites that have interesting implications during this process. In the first section, we review the situation of aging research today. Conventional theories and hypotheses about the ongoing aging process will be presented and briefly explained. The second section focuses on the nematode C. elegans and its utility in aging and nutrition research. Two useful genome editing methods for monitoring genetic interactions (RNAi and CRISPR/Cas9) are presented. Due to the mitochondria's influence on aging, we also introduce the possibility of observing bioenergetics and respiratory phenomena in C. elegans. We then report on mitochondrial conservation between vertebrates and invertebrates. Here, we explain why the nematode is a suitable model for the study of mitochondrial aging. In the fourth section , we focus on phytochemicals and their applications in contemporary nutritional science, with an emphasis on aging research. As an emerging field of science, we conclude this review in the fifth section with several studies focusing on mitochondrial research and the effects of phytochemicals such as polyphenols. In summary, the nematode C. elegans is a suitable model for aging research that incorporates the mitochondrial theory of aging. Its living conditions in the laboratory are optimal for feeding studies, thus enabling bioenergetics to be observed during the aging process.
... Age can affect weight loss after reducing feed intake [2] and the younger rats lost a higher percentage of body weight than the older mice [3]. Aging is accompanied by a host of metabolic changes, including modulation of mitochondrial function, a decline in insulin sensitivity and alterations in substrate utilization [4]. Aging encompass decrease body functions and increase death risk with increasing adult age [5]. ...
D-galactose is widely used as an inducing reagent for animal models of aging. The aging model by D-galactose induction has similarities with natural old. In this study, we described the effect of D-galactose administration in rats against their body weight. Thirty healthy male rats aged 2 months were divided into 2 groups. Control group was treated with aqua sterile as placebo, while D-galactose group was treated with 3 mg/kg BW of D-Galactose orally every day for 6 weeks. The rats in both groups were measured using digital weigher every week. The data were analyzed descriptively for the average of body weight (g) each week and statistically for the average of weight gain (%) after 6 weeks using t-test. The average of body weight in control group from week-0 until week-6 were 119± 16.24; 144± 20.24; 160± 27.37; 170± 29.08; 179± 32.79; 197± 32.37; and 208± 32.07, while in D-galactose group were 129± 13.92; 151± 15.94; 164± 24.63; 173± 25.37; 182± 27.15; 192± 25.55; and 197± 25.55. Statistical analysis using t-test showed that there was a significant difference of average weight gain in both groups (p<0.05). The average of weight gain in control group and D-galactose group was 75.59%±21.19% and 53.76%±21.79%, respectively. D-galactose could decrease the weight gain in rat model of aging.
... Along with the positive effects by DR on lipid and glucose metabolism, we showed that the flexibility in EE and RQ were much higher in the DR mice than in the AL mice. A connection between high metabolic flexibility and longevity has indeed been observed before [39]. Whether the metabolic flexibility is a result of the time frame in which the DR mice ate their food or by restricted amount of food is not known. ...
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BACKGROUND: Lifelong consumption of a Western-style diet is a risk factor for developing metabolic disorders and therefore impairs healthy aging. Dietary restriction (DR) could delay the onset of age-related diseases and prolong life span, however, the extent to which this depends on diet type is poorly understood. OBJECTIVE: To study whether feeding a Western-style diet affects the healthy aging benefits of DR. METHODS: Mice fed a Western-style diet (ad libitum and DR) were compared to those fed a standard healthy diet (ad libitum and DR). Survival and several metabolic and endocrine parameters were analyzed. RESULTS: Lifelong consumption of a Western-style diet resulted in increased adiposity, elevated triglyceride levels in plasma, higher homeostatic model assessment-insulin resistance and higher resting metabolic rate in mice compared to the standard diet group. This was accompanied by reduced survival in the Western-style diet group. DR irrespective of diet type improved abovementioned parameters. CONCLUSIONS: Lifelong restricted consumption of Western-style diet led to improved metabolic and endocrine parameters, and increased survival compared to the ad libitum Western-style diet group. Interestingly, the survival was comparable in restricted Western-style and standard diet groups, suggesting that reduced food intake rather than diet composition play more important role in promoting longevity/survival.
... (46) The Metabolic Regulation of Aging A variety of metabolic changes seen in aging, including regulation of mitochondrial activity, a decrease in insulin sensitivity, and changes in substrate use. (47) Dissecting how metabolic pathways are influenced by environmental or genetic alterations to regulate longevity may provide greater information. In mice and rats, lifelong caloric restriction (CR) can lengthen lifespan by up to 50% compared to ad libitum-fed control animals in some circumstances (48), led more studies to figure out how reducing food intake leads to longer life, and how the genetic and physiological processes mediate this effect (49). ...
BACKGROUND: Aging is an unavoidable part of life, defined by a gradual loss in tissue and organ function and an increasing chance of death. Current studies of aging connected the genetic and epigenetic changes to cause this process. CONTENT: When the aging-related epigenetic alterations is accumulated, it may result in irregulated gene expression, metabolic instability, stem cell senescence and exhaustion, and imbalance of tissue homeostasis, which all accelerate the aging process. Altered epigenetic gene regulatory mechanisms such as DNA methylation, histone modification and chromatin remodeling, and non-coding RNAs can induce aging process, thus manipulating these processes give a chance for the success of age-delaying interventions. SUMMARY: Given updated tools and technologies to investigate the epigenetic regulation affecting aging processes, new therapeutic strategies to delay this process can be developed to increase longevity and improve quality of life. KEYWORDS: aging, epigenetic, senescence, autophagy, mitochondria, metabolism, rejuvenation
Cellular senescence is a state of growth arrest where nonproliferative cells accumulate over time in the aging microenvironment under multiple external factors. Senescent cells exert a double-edged sword effect in an autocrine or paracrine manner: physiologically, they contribute to tissue development, prevent the multiplication of damaged cells and contribute to tissue repair and tumor suppression while favoring the onset of age-related diseases, including tumors. The microbiota in human tissues is intricately linked to cellular senescence and is reportedly present in the tissues of various tumors (including pancreatic tumors), closely associated with tumorigenesis and progression. The microbiota can induce cells to undergo senescence, and their long-term effects can assist senescent cells in transforming and successfully escaping senescence, contributing to tumorigenesis and progression. Here, we focus on the correlation between the microbiota, cellular senescence, and pancreatic cancer to provide novel ideas for the study and therapy of pancreatic cancer.
The old people often suffer from circadian rhythm disturbances, which in turn accelerate aging. Many aging-related degenerative diseases such as Alzheimer's disease, Parkinson's disease, and osteoarthritis have an inextricable connection with circadian rhythm. In light of the predominant effects of clock genes on regulating circadian rhythm, we systematically present the elaborate network of roles that clock genes play in aging in this review. First, we briefly introduce the basic background regarding clock genes. Second, we systemically summarize the role of clock genes in aging and aging-related degenerative diseases. Third, we discuss the relationship between clock genes polymorphisms and aging. In summary, this review is intended to clarify the indispensable roles of clock genes in aging and sheds light on developing clock genes as anti-aging targets.
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Objective Mitochondrial “retrograde” signaling may stimulate organelle biogenesis as a compensatory adaptation to aberrant activity of the oxidative phosphorylation (OXPHOS) system. To maintain energy-consuming processes in OXPHOS deficient cells, alternative metabolic pathways are functionally coupled to the degradation, recycling and redistribution of biomolecules across distinct intracellular compartments. While transcriptional regulation of mitochondrial network expansion has been the focus of many studies, the molecular mechanisms promoting mitochondrial maintenance in energy-deprived cells remain poorly investigated. Methods We performed transcriptomics, quantitative proteomics and lifespan assays to identify pathways that are mechanistically linked to mitochondrial network expansion and homeostasis in Caenorhabditis elegans lacking the mitochondrial calcium uptake protein 1 (MICU-1/MICU1). To support our findings, we carried out biochemical and image analyses in mammalian cells and mouse-derived tissues. Results We report that micu-1(null) mutations impair the OXPHOS system and promote C. elegans longevity through a transcriptional program that is independent of the mitochondrial calcium uniporter MCU-1/MCU and the essential MCU regulator EMRE-1/EMRE. We identify sphingosine phosphate lyase SPL-1/SGPL1 and the ATFS-1-target HOPS complex subunit VPS-39/VPS39 as critical lifespan modulators of micu-1(null) mutant animals. Cross-species investigation indicates that SGPL1 upregulation stimulates VPS39 recruitment to the mitochondria, thereby enhancing mitochondria-lysosome contacts. Consistently, VPS39 downregulation compromises mitochondrial network maintenance and basal autophagic flux in MICU1 deficient cells. In mouse-derived muscles, we show that VPS39 recruitment to the mitochondria may represent a common signature associated with altered OXPHOS system. Conclusions Our findings reveal a previously unrecognized SGPL1/VPS39 axis that stimulates intracellular organelle interactions and sustains autophagy and mitochondrial homeostasis in OXPHOS deficient cells.
Mutation analyses in the nematode, Caenorhabditis elegans, and mice have identified genes that increase their life-span via hormonal signal transduction, i.e. the insulin/insulin-like growth factor-1 (IGF-1) pathway in nematodes, and the growth hormone (GH)-thyriod stimulating hormone (TSH)-prolactin system in Snell dwarf mouse mutants. We have shown that the GH deficiency due to Pit1 mutation in the long-lived Snell dwarf mice may decrease circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway. The data presented are consistent with our hypothesis that the decreased circulating insulin levels resulting from the Pit1 mutation mimics a physiological state similar to that proposed to occur in the long-lived C. elegons, daf-2 mutant. Our studies demonstrate a series of changes in components of the insulin/IGF-1-signaling pathway that suggest a reduction-of-function of this pathway in the aged dwarf. These include a decreased IRS-2 pool level, a decrease in PI3K activity and its association with IRS-2 and decreased docking of p85alpha to IRS-2. Our data also suggest a preferential docking of IRS-2-p85alpha-p110alpha in the aged dwarf liver and IRS-2-p85alpha-p110beta in the aged control. We speculate that the preference for the p110alpha-containing complex may be a specific characteristic of a downstream segment of the longevity-signaling cascade. We conclude that the Pit1 mutation may result in physiological homeostasis that favors longevity, and that the Snell dwarf mutant conforms to the nematode longevity paradigm.
In the present study we have used hypopituitary Ames dwarf mice, which lack GH, prolactin and TSH, to investigate the consequences of the deficiency of these hormones on glucose homeostasis and on the initial components of the insulin signal transduction pathway in the liver. Ames dwarf mice displayed hypersensitivity to insulin since they maintained lower fasting glucose concentrations (73% of control values), had significantly reduced amounts of insulin (58% of control values), and exhibited an increased hypoglycemic response to exogenous insulin. Probably as a result of reduced insulin production, Ames dwarf mice displayed intolerance to glucose. The insulin-stimulated phosphorylation of the insulin receptor (IR) tended to be increased in the liver of Ames dwarf mice, while IR receptor protein content was increased by 38%. Insulin-stimulated phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 was increased by 61 and 72% respectively, while IRS-1 and IRS-2 protein levels were increased by 76 and 95%. The insulin-stimulated association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 was increased by 28%, but unaltered with IRS-2. Interestingly, while the insulin-stimulated phosphotyrosinederived PI 3-kinase activity was not changed, insulin-stimulated protein kinase B activation was increased by 41% in this tissue. These alterations may account for the insulin hypersensitivity exhibited by these animals. The present findings in long-lived Ames dwarf mice add to the evidence that insulin signaling is importantly related to the regulation of aging and life span.