Biogerontology
Mitochondrial dysfunction in metabolism and ageing: shared
mechanisms and outcomes?
Guillermo Lo´pez-Lluch . Juan Diego Herna´ndez-Camacho . Daniel J. Moreno Ferna´ndez-Ayala .
Pla´cido Navas
Received: 17 May 2018/Accepted: 21 August 2018
Springer Nature B.V. 2018
Abstract Mitochondria are key in the metabolism
of aerobic organisms and in ageing progression
and agerelated diseases. Mitochondria are essential
for obtaining ATP from glucose and fatty acids but
also in many other essential functions in cells
including aminoacids metabolism, pyridine
synthesis, phospholipid modifications and calcium
regulation. On the other hand, the activity of
mitochondria is also the principal source of
reactive oxygen species in cells. Ageing and
chronic age-related diseases are associated with
the deregulation of cell metabolism and
dysfunction of mitochondria. Cell metabolism is
controlled by three major nutritional sensors:
mTOR, AMPK and Sirtuins. These factors control
mitochondrial biogenesis and dynamics by
regulating fusion, fission and turnover through
mito- and autophagy. A complex interaction
between the activity of these nutritional sensors,
mitochondrial biogenesis rate and dynamics exists
and affect ageing, age-related diseases including
metabolic disease. Further, mitochondria maintain
a constant communication with nucleus
modulating gene expression and modifying
epigenetics. In this review we highlight the
importance of mitochondria in ageing and the
repercussion in the
G. Lo´pez-Lluch (&) J. D. Herna´ndez-Camacho D.
J. M. Ferna´ndez-Ayala P. Navas
Centro Andaluz de Biologı´a del Desarrollo, CABD-CSIC,
CIBERER, Instituto de Salud Carlos III, Universidad
Pablo de Olavide, Carretera de Utrera km. 1,
41013 Seville, Spain e-
mail: glopllu@upo.es
progression of age-related diseases and metabolic
disease.
Keywords Mitochondria Metabolism Ageing
Metabolic syndrome Fat Mitochondrial dynamics
ROS
Introduction
Ageing is a natural and progressive process,
occurring in all the living organisms, characterized
by the deterioration of cells, tissues and organs
affecting structure and physiology. Ageing is a
multifactorial process involving several aspects of
the cells such as genomic instability, epigenetic
alterations, telomere attrition, loss of proteostasis,
deregulation of nutrient sensing, mitochondrial
dysfunction, stem cell exhaustion, and alteration of
intracellular communication (Kennedy et al. 2014;
Lopez-Otin et al. 2013).
Mitochondria are the powerhouse of cells
providing ATP for all the activities occurring in
aerobic organisms. Their dysfunction has been
associated with many age-related diseases
(sarcopenia, type 2 diabetes (T2DM), neurological
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disorders, cardiovascular disease, liver and kidney
disease or cancer) and the functional decline
associated with ageing (Boengler et al. 2017;
Bratic and Trifunovic 2010; Fabbri et al. 2017;
Lane et al. 2015; Payne and Chinnery 2015; Ryan
et al. 2015; Wallace 2012). Further, mitochondria
are at the center of cell metabolism and their
regulation has been demonstrated to be important
in longevity in many different organisms from
yeast to primates (Lopez-Lluch et al. 2015). The
efficiency of mitochondrial activity has been
considered essential in ageing and longevity and,
in fact, a ‘‘Mitochondrial Theory’’ was coined to
explain how ageing occurs (Harman 1972).
Mitochondrial theory of ageing was immediately
associated with the widely known Free Radical
Theory of ageing that considers mitochondria as
the central sources of reactive oxygen species
(ROS) that cause the age-associated accumulation
of damaged structures during ageing (Harman
1956, 1972).
Activity, dynamics and turnover of
mitochondria depend on the energy intake and are
regulated by key factors of metabolism (Lopez-
Lluch 2017) One of these regulators is the
mammalian Target of Rapamycin (mTOR), which
is activated by high calorie intake or high levels of
aminoacids (Laplante and Sabatini 2009). The
negative regulators of mTOR are AMPactivated
kinase (AMPK) and the NAD ?-dependent protein
deacetylases, Sirtuins, that are activated when
energy uptake is limited (Hardie 2011).
The metabolic syndrome (MS) is a high-
prevalence disorder that is defined by the presence
of three or more of the following criteria: obesity
located in the abdominal region, high blood
pressure, hypertriglyceridemia, low HDL
cholesterol, and/or increased fasting glucose
(Alberti et al. 2009; Shaw et al. 2005). MS has
been associated with many ageingrelated chronic
diseases such as cardiovascular disease (Mottillo
et al. 2010; Sundstrom et al. 2006), type 2 diabetes
mellitus (T2DM) (Kahn and Flier 2000) or cancer
(Cowey and Hardy 2006). Among the main
contributors of the development of MS, insulin
resistance and abdominal obesity are considered
the most significant (Alberti et al. 2009) and are
associated with ageing progression (Huffman and
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Biogerontology
Barzilai 2009). In a transgenic mouse model,
FIRKO, disruption of the insulin receptor in
adipose tissue is associated with the increase of
longevity (Bluher et al. 2003). When compared
with wild type mice, FIRKO animals show higher
mitochondrial activity, elevated mitochondrial
DNA content, modest increases in mitochondrial
size and higher gene expression of proteins
involved in oxidative metabolism. This mouse
model suggests that mitochondrial metabolism in
white adipose tissue is important in the
progression of ageing and the development of
metabolic diseases (Katic et al. 2007).
In this article we discuss the importance of the
maintenance of mitochondrial homeostasis during
ageing and MS and how the dysregulation of these
essential organelles affects the progression of both.
Further, age-associated dysfunction of
mitochondria is hypothesized to be the key factor
that associates the appearance of MS during
ageing.
Mitochondria, structure and dynamics
Mitochondria are dynamic organelles integrated by
two membranes that define an intermembrane
space and an inner matrix. The energy production
in mitochondria relies on the electron transport
chain (ETC) that transfer high-energy electrons
from redox metabolic intermediaries such as
NADH or FADH2 originated in glycolysis, fatty-
acid oxidation and Krebs cycle, to oxygen. During
this transfer, complexes I, III and IV of the ETC
act as proton pumps from mitochondrial matrix to
the intermembrane space. Proton pumping results
in a proton gradient that generates a proton motive
force used to synthesize ATP from ADP and Pi via
the ATP synthase (complex V). Both, ETC and
ATP synthase are located in the inner membrane
of the mitochondria. For this reason, mitochondria
are the center of aerobic metabolism (Sousa et al.
2018).
The activity of mitochondria is regulated by the
demand of energy in cells. When this demand
increases, respiration rate increases promoting a
higher ATP production (Bratic and Trifunovic
2010). During this process, ETC complexes,
Biogerontology
mainly complexes I and III, can transfer electrons
directly to oxygen and produce superoxide (ROS).
For this reason, mitochondria have been also
considered an important source of intracellular
ROS production in cells (Lambert and Brand
2009). High rates of mitochondrial ROS have been
associated with the accumulation of most of the
oxidized mitochondrial macromolecules during
ageing and in many chronic diseases (Page et al.
2010).
Coenzyme Q (CoQ) is a lipid present in the
inner mitochondrial membrane that mainly
transfers electrons from complexes I and II to
Complex III. Further, changes in the levels of CoQ
have been also associated with ageing progression
(Lopez-Lluch et al. 2010). In humans, CoQ
decrease has been associate with several
mitochondrial-linked diseases and with chronic
agerelated diseases such as obesity or type II
diabetes (Hernandez-Camacho et al. 2018). A
significant reduction in the rate of CoQ
biosynthesis has been proposed to occur during the
ageing process and ageassociated diseases (Battino
et al. 1995; Beyer et al. 1985). Sedentary and
obese people show low levels of CoQ10 in plasma
probably associated with a higher risk for
cardiovascular disease (Del Pozo-Cruz et al.
2014). and the ratio of plasma cholesterol to CoQ10
has been recently suggested as biomarker of the
development of early complications of obesity in
children (Gvozdjakova et al. 2012). CoQ can be
found in a reduced form, ubiquinol (COQ10H2) and
a oxidized form, ubiquinone (CoQ 10) and it has
been demonstrated that the ratio between
reduced/oxidized CoQ10 (CoQ10H2/CoQ10) is
essential for complex I stability and ROS
production, which has been associated with the
extension of longevity (Guaras et al. 2016; Scialo
et al. 2016). For this reason, an unbalance of
CoQ10 equilibrium in mitochondria could be also
associated with mitochondrial dysfunction in
ageing and MS.
In seems clear that during ageing and MS, less
efficient mitochondria, producing less ATP and
high ROS levels, accumulate (Lopez-Lluch 2017;
Son et al. 2004). Mitochondria are very dynamic
organelles that change their shape, biogenesis
ratio, turnover and dynamics, fusion/fission
processes, depending on the bioenergetic state of
the cell (Liesa et al. 2009). Mitochondrial fusion
has been associated with active mitochondria
whereas fission is associated with damaged
mitochondria and their removal by mito/autophagy
(Lopez-Lluch et al. 2008). The main proteins
involved in fusion are large GTPases such as
mitofusins 1 and 2 (Mfn1 and Mfn2) and
autosomal dominant optic atrophy-1 (OPA1).
Mitofusins are located at the surface of the outer
membrane of mitochondria and act in the fusion
process of these membranes whereas OPA1 is an
intermembrane protein anchored to the inner
membrane and acts in the fusion of inner
membranes (Chen and Chan 2005; Olichon et al.
2002). Mfn2 also plays an important function in
tethering mitochondria and endoplasmic reticulum
(ER) playing a role in the regulation of
communication between both organelles and
endoplasmic reticulum (ER) stress and fat
accumulation in conditions of metabolic stress (de
Brito and Scorrano 2008, 2009; Naon et al. 2016).
The main proteins involved in mitochondrial
fission are the dynamin related protein 1 (DRP1)
and the fission protein 1 (FIS1). DRP1 is also a
GTPase, and is located mainly in the cytosol
although a fraction is localized at punctate
structures onto the outer mitochondria membrane
(Smirnova et al. 2001). FIS1 is a protein inserted
in the outer mitochondrial membrane that recruits
DRP1 (Santel and Frank 2008; Yoon et al. 2003).
Prohibitin is a complex of two proteins, PHB-1
and PHB-2, which has been involved in C. elegans
longevity (Lourenco et al. 2015). Prohibitins are
ubiquitous and form a ring-like complex at the
inner membrane of the mitochondria (Artal-Sanz
and Tavernarakis 2009). Prohibitins stabilize
OPA1 and then regulate mitochondrial fusion and
cristae morphogenesis. However, the exact
function of this complex in mitochondria has been
not completely clarified yet although it has been
associated with alterations of mitochondrial
function, fat metabolism and oxidative stress
response (Lourenco et al. 2015; Theiss et al. 2009)
(Fig. 1).
Mitochondrial are regulated by nutrient sensors
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 Biogerontology
In order to maintain an equilibrated activity, factor of mTOR in the regulation of cell
mitochondrial physiology must respond to the bioenergetics by inhibiting its activity directly
needs of cell metabolism. Thus, mitochondrial (Gwinn et al. 2008) or indirectly (Inoki et al.
activity, biogenesis, turnover and dynamics 2003). In general, AMPK stimulates cellular
respond to main metabolism sensors in cells such catabolism of sugars, proteins and lipids and
as mTOR, AMPK and sirtuins [for a more inhibits many anabolic enzymes affecting
comprehensive, see (Lopez-Lluch 2017; Lopez- glycogen and lipid biosynthesis (Hardie et al.
Lluch et al. 2015)]. The ubiquitous serine/ 2012).
threonine kinase mTOR is activated in high calorie Sirtuins are a protein family found in all the
intake conditions inducing anabolic activities. organisms that regulates the activity of many
Activation of mTOR has been associated with enzymes by removing acetyl residues, except in
angiogenesis, tumor development, insulin the case of mammalian SIRT4 and SIRT5 that
resistance, adipogenesis and immune cells show ADP-ribosyl-transferase activity (Santa-
activation (Laplante and Sabatini 2009). The Cruz Calvo et al. 2012). Sirtuins act as metabolic
signaling pathway triggered by mTOR is sensors by detecting fluctuations in the
downregulated by AMPK and Sirtuins that are NAD?/NADH ratio such as in the case of reduced
activated when the amount of energy is low such nutrient availability. These proteins are involved
as in low food intake, starvation or calorie in different key aspects of cell physiology from
restriction (CR). AMPK acts as an antagonistic cell cycle control to metabolism and antioxidant
Fig. 1 Importance of the
equilibrium in
mitochondrial dynamics.
Mitochondria are
maintained in a balanced
status by their control via
biogenesis, dynamics and
removal. Mitochondrial
dynamics are controlled by
the fusion/fission balance
regulated by mitofusins
(Mfn1/2), OPA1 and
prohibitins (PHB) in the
case of fusion and DRP1
and FIS1 in the case of
fission. Dysfunction in the
equilibrium of these factors
can cause the accumulation
of giant mitochondria in
senescence or small and
damaged mitochondria in
obesity. In both cases, the
reduction of CoQ
biosynthesis, decrease of
mitochondrial biogenesis,
deterioration of
supercomplexes activities
and alteration of mito/
autophagy occur decreasing
mitochondria OXPHOS
activity and increasing ROS
production

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Biogerontology
protection (Santa-Cruz Calvo et al. 2012). The
effect of Sirtuins on the mitochondrial physiology
and cell
metabolism has been associated with their effect
on longevity and part of the benefits of CR can be
explained by the activation of Sirtuins and
mitochondrial biogenesis (Guarente 2011, 2013;
Imai and Guarente 2010).
All these nutrient sensor, mTOR, AMPK and
Sirtuins, regulate the activity of the peroxisome
proliferator-activated receptor gamma coactivator
1a (PGC1a), a key transcription factor involved in
the activation of mitochondrial biogenesis. PGC1a
stimulates mitochondrial biogenesis, regulates
mitochondrial dynamics, modulates oxidative
phosphorylation, and controls mitochondrial
genome copy number (Gouspillou et al. 2014;
Handschin and Spiegelman 2006). PGC1a
regulates the expression of many transcription
factors involved in mitochondrial biogenesis and
control of respiration such as nuclear respiratory
factors 1 and 2 (NRF1 and 2),
peroxisomeproliferator activated receptor-c
(PPARc) or mitochondrial transcription factor A
(TFAM) (MartinMontalvo and de Cabo 2013).
When cells are under nutrient-limited conditions,
AMPK and SIRT1 directly activate PGC1a
through phosphorylation and deacetylation
respectively (Jager et al. 2007; Nemoto et al.
2005). SIRT1 not only activates transcriptional
activity of PGC1a by deacetylation (Rodgers et al.
2005), but also induces PGC1a expression since in
mice lacking SIRT1 PGC1a levels are also
reduced (Gerhart-Hines et al. 2007). On the other
hand, AMPK activates PGC1a by phosphorylation
and induces its own transcription via a positive
feedback loop (Jager et al. 2007) or by inducing its
deacetylation through SIRT1 activation (Canto et
al. 2010).
The activity of mitochondria is also regulated
by Sirtuins. SIRT3, a Sirtuin family member
located in the mitochondria with deacetylase
activity, is induced in skeletal muscle after CR and
its levels decrease under high-fat diet indicating
calorie-dependent regulation (Palacios et al. 2009).
SIRT3 is involved in the catabolism of lipids and
in the regulation of ETC complexes II, III and IV
activities by deacetylation (Kendrick et al. 2011),
modulation of the activity of Mn-SOD (Qiu et al.
2010), regulation of autophagy by deacetylation of
FOXO3 (Kume et al. 2010) and modulation of
mitochondrial dynamics by activating OPA1
(Samant et al. 2014).
Regarding turnover, AMPK and mTORC1
(mTOR complex 1) control the removal of
damaged mitochondria through the regulation of
autophagy and mitophagy. Whereas mTORC1
blocks autophagy by phosphorylating inhibitory
sites of unc-51-like kinase 1/2 (ULK-1 and ULK-
2), initial mediators of this process (Chan 2009;
Kim et al. 2011), AMPK induces autophagy by
phosphorylating these same proteins in their
activation sites (Alers et al. 2012). In
mitochondrial removal, Forkhead box proteins
(FoxO) proteins play an important role. FoxO are a
family of transcription factors involved in the
regulation of cell growth, proliferation,
differentiation and longevity. FoxO proteins
induce several stress response genes indicating its
important role in the induction of protective
mechanisms in organisms (Goto and Takano
2009). Regulation of FoxO proteins during ageing
and their modulation by metabolic regulators such
as mTOR, AMPK and Sirtuins associate these
proteins with the prevention of mitochondrial
dysfunction by CR, polyphenols or exercise
(Lopez-Lluch and Navas 2016).
Sestrins are another highly conserved protein
family encoded by genes known as Sens that are
upregulated after environmental stress, hypoxia
and DNA damage (Budanov and Karin 2008). In
invertebrates, only one Sens gene is found whereas
vertebrates express three different genes (Sens 1–
3). Their importance in metabolism regulation
resides in their regulation of mTORC1 activity.
Sestrins repress mTORC1 activity by activating
AMPK (Budanov and Karin 2008). Accordingly,
Sestrins have been recently proposed as
prolongevity factors after the experiments
performed in dSens-deficient D. melanogaster
(Lee et al. 2010) and in C. elegans (Yang et al.
2013). Further, inactivation of Sestrin genes in
invertebrates produces diverse metabolic
pathologies resembling accelerated aging such as
oxidative damage, fat accumulation, mitochondrial
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dysfunction, and muscle degeneration (Lee et al.
2013).
Sestrins have been recently associated with
ageing by affecting mitochondrial turnover. In
mice, Sestrins have been associated with the
regulation of metabolism producing a prolongevity
effect. These proteins are regulated by oxidative
stress through p53, NRF-2, AP-1 and FoxO and
they regulate several components that reduce ROS
production, increase mitochondrial biogenesis and
induce mitophagy increasing the efficiency of the
oxidative metabolism (Lee et al. 2013). Transgenic
mice deficient in Sens2 and Sens3 genes have
demonstrated the important role of these proteins
in the regulation of lipid metabolism and the
suppression of age and obesity-associated
mitochondrial disorders (Bae et al. 2013; Lee et al.
2012). Sesn2 KO mice show higher glucose
intolerance, lower insulin response and
development of hepatosteatosis (Lee et al. 2012).
Sestrins-dependent mTOR Complex I (mTORC1)
inactivation through activating AMPK is critical in
the maintenance of autophagy and the elimination
of dysfunctional mitochondria (Ishihara et al.
2013). On the other hand, Sens3 has been recently
associated with the activation of mTORC2 and
Akt phosphorylation enhancing insulin sensitivity
and glucose metabolism (Tao et al. 2015). During
aging Sestrin levels decrease in muscle and
aerobic physical exercise is able to restore Sestrin
2 levels in mice muscle restoring the capacity to
respond to insulin and autophagy (Lenhare et al.
2017), As Sestrins are regulated by many stress
factors including ROS, these proteins emerge as
interesting regulators of mitochondrial turnover
and ageing-related diseases by mild stress as
hormetic response (Wang et al. 2017). In humans,
a recent article indicates that Sestrin 1 and 3
decreased in aged muscle although mRNA levels
of SESN1 (Zeng et al. 2018). A very recent study
also demonstrate that muscle from frail elderly
people show significant reductions of Sestrin1 and
Sestrin2 indicating the importance of these factors
in the maintenance of muscle capacity during
aging (Rai et al. 2018).
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Biogerontology
Mitochondrial activity and turnover are affected
during ageing
Many evidences indicate that mitochondria play
key roles in the pathophysiology of ageing and in
earlier stages of events leading to the ageing
phenotype (Gonzalez-Freire et al. 2015; Kennedy
et al. 2014; Lopez-Otin et al. 2013). Damaged
mitochondria showing low ATP production and
high release of ROS are associated with ageing
and age-related diseases that show dysregulation
of mitochondrial dynamics and turnover
(Chistiakov et al. 2014; LopezLluch 2017; Merry
2002).
A factor involved in mitochondrial dysfunction
during ageing is the rate of superassembly of the
respiratory chain complexes. ETC complexes can
be organized in larger structural and functional
units named as ‘‘respirasome’’ already found in
bacteria and in mitochondrial membranes. This
supra-organization permits the reduction of
diffusion distances of substrates and a more
effective flow of electrons through the ETC. It has
been suggested that age-associated destabilization
of supercomplexes of ETC might be important for
the development of mitochondrial ageing
phenotype and in particular in post-mitotic tissues
(Gomez and Hagen 2012). Mitochondrial ETC
complexes can release ROS by transferring
electrons directly to molecular oxygen (Goncalves
et al. 2015), and the assembly state of these
complexes has been associated with the rate of
ROS production in mitochondria (Genova and
Lenaz 2015; MorenoLoshuertos and Enriquez
2016). Consequently, the incapacity to build
supercomplexes or their progressive deterioration
could be one of the causes of the increase in
mitochondrial ROS production during ageing
(Dencher et al. 2007; Genova and Lenaz 2015).
Maintenance of the quality control of
mitochondria is considered a crucial factor to
counteract ageing process (Romanello and Sandri
2015; Weber and Reichert 2010). Accumulation of
damaged mitochondria during ageing is associated
with the decline of the mitochondrial turnover
through inhibiting mitophagy; a specific
autophagy process that removes damaged
mitochondria (Chistiakov et al. 2014). Then, it
Biogerontology
seems clear that removal of defective
mitochondria is essential to maintain cellular
homeostasis. In this role, the BCL-2 Interacting
Protein 3 (BNIP3) and BNIP3/ NIX homologue in
C. elegans (DCT-1) is key in mediating mitophagy
and to increase longevity (Palikaras et al. 2015). In
this role, ubiquitination of BNIP3 by PTEN
Induced Putative Kinase 1 (PINK1)/ E3 Ubiquitin-
Protein Ligase (PARKIN) pathway is essential for
the removal of damaged mitochondria by
mitophagy (Harper et al. 2018). Further, damaged
mitochondria activate SKN-1/Nuclear factor
erythroid-derived-like 2 (NRF-2) pathway in C.
elegans (Fang et al. 2017), initiating a bipartite
retrograde signaling pathway that stimulates the
coordinated induction of both mitochondrial
biogenesis and mitophagy (Palikaras et al. 2015),
indicating the importance of a balance between the
generation of new mitochondria and the removal
of damaged structures to increase longevity
(Denzer et al. 2016). The renovation of
mitochondrial network plays also a key role in
health-span increase after CR (LopezLluch et al.
2008). Prolongevity effectors such as CR, exercise
and polyphenols prevent the accumulation of
to cell senescence accompanied by the
accumulation of damaged mitochondria showing
lower mitochondrial potential and higher ROS
production (Lee et al. 2007; Park et al. 2010).
These evidence highlight the importance of the
presence of a functional fission machinery to
remove damaged mitochondria by mito/autophagy
damaged mitochondria by inducing mito- and
autophagy (Lopez-Lluch and Navas 2016) (Fig. 2).
Several studies suggest that ageing affects the
equilibrium of mitochondrial dynamics affecting
fusion and fission. Senescence has been associated
with the accumulation of giant dysfunctional
mitochondria characterized by highly
interconnected networks and ultrastructural
abnormalities (Beregi and Regius 1987)
accompanied by higher production of ROS and
lower mitochondrial respiratory activity (Yoon et
al. 2006). Accordingly, blocking fission process by
depleting FIS1 or inhibiting DRP1 leads
Fig. 2 Prolongevity factors prevent the accumulation of
damaged mitochondria by inducing the activity of
molecular regulators of mitochondrial turnover. A balanced
turnover of mitochondria is essential to avoid the
accumulation of damaged mitochondria. Accumulation of
damaged mitochondria is the main factor of mitochondrial
dysfunction during aging and metabolic syndrome. Caloric
restriction, bioactive compounds such as polyphenols and
others and physical activity induce the activity of different
factors which stimulate the biogenesis of new mitochondria
and the elimination of damaged structures by
mito/autophagy. Dysregulation of these molecular factors
by ageing or metabolic syndrome produces the
accumulation of damaged mitochondria and mitochondrial
dysfunction
(Gomes and Scorrano 2008; Twig et al. 2008). A
lower fission rate would allow mitochondria to
escape autophagic degradation and to maintain
ATP production but with higher ROS production
during ageing (Gomes and Scorrano 2011).
Interestingly, fission proteins FIS1 and DRP1
levels increased in liver of a CR mouse model
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(40% CR for 6 months), whereas no changes were
found in fusion-related proteins (Mfn1/2 and
OPA1) (Khraiwesh et al. 2013). Considering the
increase of mitochondrial biogenesis found in CR
conditions (Lopez-Lluch et al. 2006; Nisoli et al.
2005), the increase in fission-related proteins as a
prolongevity mechanism would permit the
removal of damaged mitochondria and the
regeneration of the mitochondrial network
(Khraiwesh et al. 2013; Lopez-Lluch et al. 2008).
For more detailed information about the role of
changes of mitochondrial dynamics in longevity,
see (Sebastian et al. 2017).
In summary, multiple factors affects
mitochondrial activity and many of them have
been associated with cell senescence and ageing as
has been recently reviewed (Ziegler et al. 2015).
The identification of these factors will be essential
to understand how their deregulation affects the
progression of ageing and many pathological
situations. Among them, PGC-1b emerges as one
interesting candidate by controling basal
mitochondrial biogenesis and mitochondrial fusion
through the modulation of Mfn2 (Liesa et al.
2008). For example, in a heart-selective PGC-
1bdeficient murine model, age-dependent cardiac
phenotypes have been associated with the increase
of mitochondrial dysfunction (Valli et al. 2017)
(Fig. 2).
Mitochondrial dysfunction is associated
with metabolic syndrome
One of the characteristics of ageing is the
accumulation of visceral adiposity in elderly
people (Matsumoto 2002). Accumulation of
visceral fat is associated with greater morbidity
due to the increase of risk for cardiovascular
disease, hypertension and T2DM. Obesity and
T2DM are also considered agerelated diseases.
Obesity is associated with the dysfunction of
adipose tissue characterized by adipocyte
hypertrophy, proinflammatory conditions, and
insulin resistance. Additionally, the incapacity to
respond to insulin induces ectopic fat deposition in
other organs producing lipotoxicity in muscle,
liver and also pancreas, a phenomenon that has
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Biogerontology
been also associated with ageing (Matsumoto
2002). Mitochondrial dysfunction is also present in
obesity-related diseases such as insulin resistante
and type 2 diabetes mellitus, indicated by low
expression of mtDNA and reduction of the levels
of mitochondrial complexes affecting all the main
organs involved in the development of metabolic
syndrome such as muscle, liver and adipose tissue
(Patti and Corvera 2010; Schottl et al. 2015).
Mitochondrial dysfunction also reduces the
capacity to oxidize fatty acids (Patti and Corvera
2010; Toledo and Goodpaster 2013). The
deficiency in the capacity of mitochondria to
metabolize lipids has been proposed to predispose
muscle, liver and adipose tissue to accumulate
lipids, especialy long-chain fatty acids (Hafizi Abu
Bakar et al. 2015), and then, to aggravate insulin
resistance (Lowell and Shulman 2005). Recently,
it has been proposed that lowering serum FFAs
levels and improving mitochondrial function may
improve insulin response in youth with T2D.
Obesity is also associated with the metabolic
impairment in the capacity to transit between fatty
acid and glucose metabolism, known as
‘‘metabolic inflexibility’’ (Griffin et al. 2015), that
is present in obese people since they oxidize lipids
instead of glucose in insulin-stimulated conditions
(Storlien et al. 2004). So, the accumulation of
damaged mitochondria would explain the increase
of ROS in skeletal muscle associated with insulin
resistance in obese individuals and the appearance
of T2DM and muscle dysfunction during normal
ageing (Barbieri et al. 2013).
Mitochondrial dynamics are also affected in
obesity-related diseases. Reduced expression of
Mfn2 has been found in skeletal muscle in obese
and T2DM patients (Bach et al. 2005) and has
been associated with the fragmentation of the
mitochondrial network and the decrease of
membrane potential in mitochondria (Pich et al.
2005). Mitochondrial fragmentation and down
regulation of fusion have been also detected in
T2DM and obese subjects associated with
impaired bioenergetics (Bach et al. 2005). The
reduction of fusion together with the increase in
fission indicates that there is a shift toward fission
of mitochondria in obesity and obesity-related
diseases. Decrease of Mfn2 plays an essential role
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in mitochondrial dysfunction associated with fat
accumulation. A screen of differentially expressed
genes from skeletal muscle of obese rats has
identified Mfn2 as a suppressor of obesity (Bach et
al. 2003). Mfn2 KO cells show lower
bioenergetics efficiency indicated by lower
glucose oxidation and mitochondrial respiration
(Bach et al. 2003) that can be associated with the
progression of obesity by reducing energy
expenditure and increasing fat store (Liesa et al.
2009). On the contrary, conditions that increase
energy expenditure such as cold exposure, chronic
exercise or nutraceuticals as resveratrol induce
Mfn2 expression in skeletal muscle and brown
adipose tissue (Cartoni et al. 2005; Dolinsky et al.
2013; Soriano et al. 2006). Interestingly, all these
conditions are known to induce SIRT1 that has
been recently shown to suppress mitochondrial
dysfunction in a model of ischemia by modulating
Mfn2 activity by deacetylation indicating a
connection between SIRT1dependent
mitochondrial regulation and mitochondrial fusion
(Biel et al. 2016). Further, Mfn2 also participates
in the maintenance of CoQ10 synthesis and could
be also important in the regulation of CoQ 10 levels
during ageing and obesity (Mourier et al. 2015).
However, to date no data are available about its
relationship in obesity or ageing indicating the
need of further research.
On the other hand, higher mitochondrial fission
has been associated with fat accumulation in
genetically induced obesity (ob/ob) mice or in
high-fat induced obesity (Jheng et al. 2012) and
with insulin resistance in another mice model of
obesity (db/db) (Holmstrom et al. 2012). These
studies indicate that obesity is associated with the
accumulation of small and inefficient
mitochondria that are unable to metabolize lipids
and are, at least in part, responsible of the
dysregulation of insulin signaling in cells. In a
vicious circle, insulin resistance can increase
mitochondrial dysfunction and aggravate obesity
as has been recently demonstrated in a double KO
mice model for insulin and insulin-growth factor 1
receptors (Viana-Huete et al. 2018). On the other
hand, disruption of mitochondrial fission in liver
can protect mice from diet induced obesity and
metabolic deterioration indicating the importance
of fission in the accumulation of damaged
mitochondria (Wang et al. 2015).
Evidence suggests that Sestrins could be
considered key factors in the control of
mitochondrial homeostasis during ageing and
obesity. Inactivation of Sestrins in invertebrates
results in metabolic pathologies that include
oxidative damage, mitochondrial dysfunction and
fat accumulation (Lee et al. 2013). However, to
date, there is no information available about the
activity of Sestrins in adipose tissue and its
behavior during ageing. Indirect evidences
indicate a putative role of this family of proteins in
fat accumulation. Resveratrol (RSV) prevents lipid
accumulation in liver avoiding Liver X receptor
(LXRa)-mediated hepatic lipogenesis by inducing
Sens2 gene (Jin et al. 2013). LXRa is a
transcription factor that regulates lipid synthesis in
liver (Joseph et al. 2002) and insulinstimulated
lipogenesis (Chen et al. 2004). LXRa induces the
expression of fatty acid synthesis (FAS), acetyl-
CoA carboxylase (ACC) and sterol regulatory
element binding protein 1c (SREBP-1c) (Grefhorst
et al. 2002; Repa et al. 2000). Then, the
Sens2dependent repression of LXRa in liver or
adipose tissue by RSV would indicate a key role of
these proteins in fat accumulation during ageing.
On the other hand, in old mice, Sens2 is induced in
muscle by acute aerobic exercise accompanied by
an increase in autophagy and probably
contributing to the improvement of insulin
sensitivity (Lenhare et al. 2017).
Among the regulators of metabolism, AMPK
plays an important role in the progression of MS
and insulin resistance in white adipose tissue
(WAT). Phosphorylated AMPK controls the
activity of many downstream substrates involved
in the increase in lipid oxidation and the uptake of
glucose (Jager et al. 2007). Thus, deficiency in
AMPK results in glucose intolerance, lower
physical capacity and obesity (Steinberg et al.
2010). Taken into consideration the central role of
AMPK in the control of metabolism and
mitochondria (Burkewitz et al. 2014), the decrease
of its levels and activity during ageing could
explain the deterioration of the physiology of
adipose and other tissues during aging in the
elderly (Ruiz et al. 2016). Regarding this aspect, a
123

new regulator of AMPK, the prolyl isomerase,
Pin1, has been found to increase in high fat
conditions (Nakatsu et al. 2011). Pin1 KO mice
show a high fat diet-induced obesity resistant
phenotype (Nakatsu et al. 2015). Interestingly,
deregulation of Pin1 has been also associated with
ageing and age-related diseases (Lee et al. 2011)
and downregulation of its levels are associated
with senescence in human tendon stem cells (Chen
et al. 2015) although more research is needed to
associate reduction of activity of Pin1 with ageing
and age-related diseases.
All these studies suggest that mitochondrial
dysfunction is the common denominator in ageing
and fat accumulation. Metabolic dysfunction
associated with the accumulation of damaged
mitochondria is one of the main factors in the
evolution of T2DM, fat accumulation in muscle,
WAT or liver and the increase of oxidative stress.
The study of factors involved in the improvement
of mitochondrial dynamics in order to increase
mitochondrial turnover and to improve
mitochondrial architecture and function is
essential to develop therapeutic strategies in order
to improve fat accumulation-related diseases.
Metabolic activity can be regulated by epigenetic
mechanisms
Gene expression is regulated by modifications in
DNA and histones. The addition of a methyl group
to cytosine results in the formation of 5-
methylcytosine (5-mC), which is one of the
heritable epigenetic marks. DNA methylation has
been proposed as the most promising molecular
marker for monitoring ageing and predict life
expectancy (Horvath 2013). However, the
mechanisms underlying age-related DNA
methylation changes are still unknown.
The initial establishment of DNA methylation
patterns takes place during development just after
the massive demethylation that takes part on the
preimplantation embryo genome re-establish cell
totipotency (Feng et al. 2010). DNA methylation
patterns are maintained or change along life by
methylation and demethylation processes
depending on different factors (Clark 2015;
123
Biogerontology
Schubeler 2015). One of the most crucial factors
that modify DNA methylation patterns is the
environment (Feil and Fraga 2012; Leenen et al.
2016), although the mechanisms behind this
influence must be clarified. DNA methylation
changes are associated with pollutants, UV
radiations and temperature, viral infections and
microbiota, mood disorders, lifestyle, overeating,
high-fat diet, famine, caloric restriction, physical
activity and circadian rhythms (Feil and Fraga
2012; Grazioli et al. 2017; Leenen et al. 2016).
Comparative analyses carried out in twin pairs
demonstrated that the methylation status gradually
diverges with age as a consequence of different
environments and lifestyles (Fraga et al. 2005).
Recently it has been proposed the ‘‘Epigenetic
Theory of Ageing’’, which is the result of two
opposing phenomena: (1) baseline DNA
methylation levels progressively diverge during
ageing (Fraga et al. 2005), and (2) some locus-
specific DNA methylation changes are highly
reproducible across aged people, independently of
gender and tissue type (Horvath 2013). While
environmental factors are responsible of such
DNA methylation pattern divergence (Feil and
Fraga 2012; Leenen et al. 2016), it seems that in
later stages of life the whole process paradoxically
culminates in a convergence of epigenomes,
leading to a programmed epigenetic
reconfiguration during ageing that had been
postulated as the ‘‘epigenetic clock’’ theory
(Horvath 2013).
Therefore, the environment and the signals we
receive during development determine the
epigenetic marks which will make us more prone
to suffer certain diseases and to determine the
process by which we will age. Many of these
signals are related with metabolism. Dietary habits
during pregnancy strongly determine the genome
methylation status of offspring (Aagaard-Tillery et
al. 2008). The offspring of a mother exposed to
famine had an increased incidence of several
health problems associated with metabolism such
as obesity, hypertension, diabetes and
cardiovascular diseases, whereas children from
mothers with depression seems to be predisposed
to higher risk of chronic diseases during adulthood
(Ciccarone et al. 2017). On the other hand, some
Biogerontology
environmental or behavioral factors induce
beneficial epigenetic outcomes via changes of
DNA methylation patterns. Long-term physical
activity changes the methylation of several genes
involved in metabolism, muscle growth,
haematopoiesis and inflammation, reducing cancer
risk and mortality (Ciccarone et al. 2017; Grazioli
et al. 2017; Lapinska et al. 2018).
A number of genes are hypermethylated with
age and with other age-related diseases indicating
their relationship with gene regulation during
ageing (Lapinska et al. 2018; Zampieri et al.
2015). Many of these genes are involved in
metabolism regulation related with cell survival as
has been demonstrated in mitochondrial diseases
independently of the etiology and the organism.
Interestingly, this response is the same in human
fibroblasts (Fernandez-Ayala et al. 2013) and in
the fruit fly Drosophila melanogaster (Fernandez-
Ayala et al. 2010) indicating the importance of
metabolism regulation during ageing.
Mitochondria has been associated with the
epigenetic regulation during development mainly
affecting protective genes such as mitochondrial
chaperones, control proteases and xenobiotic
response components that comprise the
mitochondrial unfolded protein response (UPR mt)
(Tatar and Sedivy 2016). Mild mitochondrial
stress has been associated with changes in the
epigenome affecting chromatin reorganization
involved in the maintenance of UPRmt and
increasing longevity in C. elegans (Tian et al.
2016). Epigenetic modifications involved
methylation of histones (H3K9me1/2) have been
associated with the regulation of energy
expenditure and fat storage in these animals
(Meister et al. 2011) indicating a communication
between mitochondrial activity and energy
regulation and the control of the expression of
genes involved in longevity. Therefore, a
reduction in the activity of the UPR mt can be
responsible of the accumulation of damaged
proteins in dysfunctional mitochondria in ageing
and in age-related neurodegenerative diseases
(Moehle et al. 2018). However, it seems that
UPRmt activation alone is not sufficient to prolong
life-span (Bennett et al. 2014; Rauthan et al.
2013), although it is essential in the maintenance
of mitochondrial activity in stem cell maintenance,
immune response, metabolic adaptations to
physiological changes and ageing (Lin and Haynes
2016).
Mitochondria and metabolism are regulated by
prolongevity factors
Much evidence indicates that the maintenance of
mitochondrial activity is crucial to delay ageing
process. In fact, the decline in mitochondrial
turnover has been associated with the impairment
of mitochondrial biogenesis during ageing,
especially in high energy demanding tissues such
as muscle, brain or heart (Conley et al. 2000; Short
et al. 2005). Several interventions such as CR,
bioactive compounds such as polyphenols or
physical activity increase mitochondrial turnover
inducing the synthesis of new mitochondrial
structures while eliminate damaged elements by
autophagy highlighting the important role of the
maintenance of the mitochondrial physiology
during ageing (Baur et al. 2010; de Cabo et al.
2014; Feige et al. 2008; Rodriguez-Bies et al.
2015). Further, one recent review emphasized the
role of autophagy in the prolongevity effect of CR
or bioactive compounds such resveratrol,
spermidine and rapamycin (Das et al. 2017). This
effect has been associated with the inhibition of
mTOR and activation of Sirtuins (Szafranski and
Mekhail 2014). Further, the inductor of
mito/autophagy FOXO3 is also induced in CR
conditions regulating different mechanisms
involved in cell survival (Willcox and Willcox
2014). Studies performed in non-obese humans
under 25% CR has highlighted the importance of
the regulation of metabolism as indicated by
weight loss, reduction of resting metabolic rate
and many other markers (Ravussin et al. 2015).
The benefits from CR in ageing and associated
comorbidities has been directly associated to
changes in metabolism during fasting periods
(Mattson et al. 2018). Intermittent metabolic
switching is defined as fasting or exercise periods
when the transition from glucose to fatty acids and
ketone bodies. Mattson et al. 2018 propose that
switching between negative energy balance
123

(exercise or fasting) and positive balance (eating
and resting) could improve health parameters such
as insulin sensitivity, abdominal fat, resting heart
rate, blood pressure and muscle mass. In this
process mitochondrial physiology plays an
important role since intermittent metabolic
switching incite mitochondrial biogenesis in
neurons through the activation of PGC1a. During
metabolic switching in fasting or vigorous
exercises states, mTOR activity tends to be
reduced while AMPK is inducing autophagy.
Further, very recently, a low-carbohydrate,
ketogenic diet extended longevity in adult male
mice preserving motor function, muscle mass and
memory in aged animals in an effect associated
with the decrease of mTOR downstream signaling
(Roberts et al. 2018).
CR can be mimicked by different bioactive
compounds. In a yeast model rapamycin
significantly increased lifespan by 87% and
resveratrol and dapsone showed a tendency to
increase lifespan (Choi et al. 2013). Resveratrol
also showed capacity to increase lifespan of
middle-aged mice on a high calorie diet,
improving insulin sensitivity (Baur et al. 2006). In
this model, resveratrol increased the activity of
AMPK and PGC-1a, mitochondrial number and
motor function. This same effect was found in
muscle by activating SIRT1 and PGC-1a (Lagouge
et al. 2006).
It is also clear that physical activity prevents
muscle changes involved in frailty in elderly
people such as sarcopenia, although these
alterations can be also associated to chronic disuse
instead to muscle ageing. It is clear that
maintenance of muscle mass reduces the risk of
fall, functional decline, feeling of weakness and
dependence (Garatachea et al. 2015; McKendry et
al. 2018; Wroblewski et al. 2011). At the
molecular level, many research has demonstrated
that exercise affects mitochondrial biogenesis
(Vina et al. 2009), mitochondrial fragmentation
and autophagy in a mechanism dependent on
PGC-1a activity (Halling and Pilegaard 2017;
Halling et al. 2017), and ETC activity and
mitochondrial content (Menshikova et al. 2006)
among others. These evidence clearly indicate the
potential of physical activity as prolongevity
123
Biogerontology
intervention by modulating bioenergetics and
maintaining mitochondrial activity.
In general, all the prolongevity interventions,
CR, bioactive compounds, or exercise, induce
modifications in mitochondrial physiology
activating mitochondrial biogenesis at the same
time that induce the removal of mitochondrial
structures through mito/ autophagy. These models
indicate that activation of mitochondrial turnover
is key in longevity.
Circadian rhythm and mitochondrial activity
Circadian rhythm is affected during aging and
metabolic disease (Borengasser et al. 2014;
Weinert 2010). During aging, a reduction in the
amplitude of circadian body temperature rhythms
occurs (Weinert 2010). On the other hand,
offspring fed with high fat diet from obese dams
showed suppression in circadian and metabolic
genes in comparison with offspring from lean
dams (Borengasser et al. 2014). These
perturbations of the circadian rhythm increase
oxidative damage to proteins and lipids, decrease
of the capacity
forfreeradicalscavengingandimpairedmitochondria
l function (Jagota and Kalyani 2010; Weinert
2010). In this regulation administration of
melatonin, an hormone known to control the
circadian rhythm, affected diary rhythms of lipid
peroxidation and antioxidant enzymes in male rat
liver indicating the link with mitochondrial
activity (Manikonda and Jagota 2012).
Biological rhythms are regulated by many
nuclear transcription factors. One of these factors
is the circadian locomotor output cycles kaput
(CLOCK)delta19. Dysruption of this gene in mice
causes the reduction of PGC1a and decrease in the
amount of the mitochondrial transcription factor-A
accompanied by the decrease of mitochondria
(Pastore and Hood 2013). This mutation also
affects mitochondrial gene expression in young
mice livers (Gong et al. 2015). Further, changes in
mitochondrial morphology, fusion and fission
processes as well as generation of new
mitochondria are dependent of circadian clock (de
Goede et al. 2018). In cells, master clock gene
Biogerontology
Aryl Hydrocarbon Receptor Nuclear Translocator
Like/ Brain and Muscle ARNT-Like 1
(ARNTL/BMA1) silencing affects the rhythm of
mitochondrial phosphorylation during the day
whereas mitochondrial dysfunction deregulates the
rhythmic clock-gene expression in reciprocal
interplay (Scrima et al. 2016). On the other hand,
mitochondrial alterations with 3-nitropropionic
acid induce severe circadian deficit in behavior
(Kudo et al. 2014). All these studies indicate an
important relationship between mitochondrial
activity and circadian rhythm in cells and tissues.
In the relationship between circadian rhythm
and mitochondria, sirtuins and AMPK play an
important role. A circadian clock of NAD ?
biosynthesis through modifications of
mitochondrial protein acetylation that synchronize
mitochondrial activity with fasting and feeding
cycle has been recently proposed (Peek et al.
2013). Levels of NAD? can affect the activity of
complex I by deacetylation (Cela et al. 2016).
Interestingly, sirtuins have been associated with
the control of the circadian rhythms through their
activity in the central nervous system (Ramadori
and Coppari 2010). Neurons mainly located in
hypothalamus coordinate long-term energy and
glucose balance (Elmquist et al. 2005), by sensing-
mechanisms able to respond to hormonal and
nutrient levels. Since SIRT1 is known to respond
to these variations in peripheral tissue, it has been
proposed that this deacetylase can affect nutrient
response in neurons. In fact, SIRT1 activity in
brain is influenced by changes in nutrient
availability and affected by obesity (Cohen et al.
2004; Ramadori et al. 2008). Further, AMPK also
mediates the effects of agents acting on the
hypothalamus promoting feeding and circadian
rhythms of metabolism (Hardie et al. 2012). It is
then clear that the mechanisms that maintain
mitochondrial dynamics and turnover are involved
in the regulation of circadian rhythms and that
disruption of these mechanisms can be involved in
the dysfunction of these rhythms during aging and
metabolic disease. At the same time, in a vicious
cycle, dysregulation of circadian rhythms affect
mitochondrial activity promoting its malfunction.
Concluding remarks
Much evidence indicate that maintenance of
bioenergetics homeostasis associated with
mitochondrial activity is key to delay ageing and
prevent ageassociated diseases (Riera et al. 2016).
Regulation of nutrient sensors such as mTOR,
AMPK and Sirtuins are in the center of this effect.
These sensors are key in the regulation of the
complex equilibrium between mitochondrial
biogenesis, dynamics and turnover. During ageing
a tendency to increase fusion in mitochondria has
been reported in order to maintain mitochondrial
activity, however, fat accumulation induces a
higher activity of fission and a block in mitophagy
promoting the accumulation of small and damaged
mitochondria.
Probably these two opposite processes end in
the accumulation of damaged and ineffective
mitochondria that increase oxidative damage and
are related with insulin resistance, metabolic
dysfunction and the secretion of proinflammatory
mediators. In a vicious cycle, insulin resistance
and proinflammatory cytokines promotes damage
of mitochondria. Then, the study of the regulation
of metabolic mediators and the effects of
prolongevity factors such as CR, bioactive
compounds or exercise will help us to develop
therapeutic strategies to delay ageing and the
damaging effect of fat accumulation.
Funding The research group is funded by the Andalusian
Government Grant BIO177 (FEDER funds of European
Commission). Research has been funded by the Spanish
Ministry of Economy and Competitiveness Grant
DEP201239985 and Instituto de Salud Carlos III FIS Grant
PI14/01962. Authors are also members of the CIBERER,
Instituto Carlos III, of the Spanish Ministry of Health.
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