Received: 15 October 2019 Accepted: 30 November 2019

DOI: 10.1111/obr.12991

ETIOLOGY AND PATHOPHYSIOLOGY

Obesity and ageing: Two sides of the same coin

Bjorn T. Tam1,2 | Jose A. Morais1,3 | Sylvia Santosa1,2,4

1
Department of Health, Kinesiology, and
Applied Physiology, Concordia University, Summary
Quebec, Montreal, Canada Conditions and comorbidities of obesity mirror those of ageing and age-related dis-
2
Metabolism, Obesity, and Nutrition Lab,
eases. Obesity and ageing share a similar spectrum of phenotypes such as com-
PERFORM Centre, Concordia University,
Quebec, Montreal, Canada promised genomic integrity, impaired mitochondrial function, accumulation of
3
Division of Geriatric Medicine and Research intracellular macromolecules, weakened immunity, shifts in tissue and body composi-
Institute, McGill University Health Centre,
Quebec, Montreal, Canada tion, and enhanced systemic inflammation. Moreover, it has been shown that obesity
4
Research Centre, Centre intégré universitarie reduces life expectancy by 5.8 years in men and 7.1 years in women after the age of
de santé et de services sociaux du Nord-de-
40. Shorter life expectancy could be because obesity holistically accelerates ageing at
I'Île-de-Montréal, Hôpital du Sacré-Cœur de
Monréal (CIUSS-NIM, HSCM), Quebec, multiple levels. Besides jeopardizing nuclear DNA and mitochondrial DNA integrity,
Montreal, Canada
obesity modifies the DNA methylation pattern, which is associated with epigenetic
Correspondence ageing in different tissues. Additionally, other signs of ageing are seen in individuals
Sylvia Santosa, PhD, RD, Department of
with obesity including telomere shortening, systemic inflammation, and functional
Health, Kinesiology, and Applied Physiology,
Concordia University, Loyola Campus, SP declines. This review aims to show how obesity and ageing are “two sides of the same
165.21, 7141 Sherbrooke Street West,
coin” through discussing how obesity predisposes an individual to age-related condi-
Montreal, QC, H4B 1R6, Canada.
Email: s.santosa@concordia.ca tions, illness, and disease. We will further demonstrate how the mechanisms that
perpetuate the early-onset of chronic diseases in obesity parallel those of ageing.
Funding information
Horizon Postdoctoral Fellowship; Canada
Research Chair - Tier 2, Clinical Nutrition KEYWORDS

age-related diseases, ageing, obesity

ABBREVIATIONS: AD, Alzheimer's disease; Akt, Protein kinase B; AMPK, AMP-activated protein kinase; apoE4, ε4 allele of apolipoprotein E; AREG, amphiregulin; Atg, autophagy related; Bcl-2,
B-cell lymphoma 2; CCL2, C–C motif chemokine ligand 2; CCL20, C–C motif chemokine ligand 20; CCL27, C–C motif chemokine ligand 27; CCR7, C–C chemokine receptor type 7; CD, Cluster
of differentiation; CRP, C-reactive protein; CVD, cardiovascular disease; CXCR3, Chemokine receptor 3; DAG, diacylglycerol; DAMPs, damage-associated molecular patterns; DDR, DNA damage
response; DNAm age, DNA methylation age; DNMT3a, DNA methyltransferase 3 alpha; ETC, electron transport chain; F4/80, EGF-like module-containing mucin-like hormone receptor-like 1;
FFA, free fatty acid; FTO, obesity-related gene; GAD, glutamic acid decarboxylase; GDF15, growth/differentiation factor 15; H3K27me3, trimethylation of lysine 27 on histone H3; HDL-C, high-
density lipoprotein cholesterol; HFD, high-fat diet; HIF-1α, hypoxia-inducible factor 1 alpha; HMGB1, High mobility group box 1; IA-2, Protein tyrosine phosphatase, receptor type N; IFN-γ,
interferon gamma; IGF-1, insulin-like growth factor 1; IKK, I kappa B kinase; IL-10, interleukin-10; IL-1α, interleukin- 1 alpha; IL-6, interleukin- 6; IL-8, interleukin- 8; IRS-1, insulin receptor
substrate 1; JNK, c-Jun N-terminal kinase; LDL-C, low-density lipoprotein cholesterol; LFA-1, lymphocyte function–associated antigen 1; MCP-1, monocyte chemoattractant protein-1; MDM2,
E3 ubiquitin-protein ligase; MiDAS, dysfunctional mitochondria mitochondrial dysfunction–associated senescence; MIP-1α, macrophage inflammatory protein 1 alpha; MMP-1, matrix
metalloproteinase-1; MMP-3, matrix metalloproteinase-3; mtDNA, mitochondrial DNA; mTOR, mammalian target of rapamycin; MuRF-1, muscle RING-finger protein-1; nDNA, nuclear DNA;
NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; OXPHOS, oxidative phosphorylation; p16INK4a, cyclin-dependent kinase inhibitor 2A; p21, cyclin-dependent kinase inhibitor
1; p53, tumour protein 53; p62, sequestosome-1; PAI-1, plasminogen activator inhibitor-1; PD-1, programmed cell death protein 1; PGC-1α, peroxisome proliferator-activated receptor gamma
coactivator 1 alpha; Pho, rhodopsin; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PPARγ, peroxisome proliferator-activated receptor gamma; PTEN, phosphatase and tensin homolog;
ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; Satb1, special AT-rich sequence-binding protein-1; SA-β-gal, senescence-associated beta-galactosidase; SOD,
superoxide dismutase; SPINK1, serine protease inhibitor kazal-type 1; SREBF-1, sterol regulatory element binding transcription factor 1; T2DM, type 2 diabetes mellitus; TNF-α, tumour necrosis
factor alpha; TUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling; VEGF, vascular endothelial growth factor; VLDL-C, very low-density
lipoprotein; γ-H2AX, H2A histone family member X.

Obesity Reviews. 2020;1–21. wileyonlinelibrary.com/journal/obr © 2020 World Obesity Federation 1

2 TAM ET AL.
1 | I N T RO DU CT I O N
1
Obesity increases the risk of premature death by 1.45 to 2.76 fold
and shortens lifespan by up to 20 years.2,3 We hypothesize that the
shorter life expectancy observed in obesity is partially attributable to
the fact that obesity accelerates ageing, as conditions and com-
orbidities of obesity mirror those of ageing and age-related diseases.
Adults with obesity are at higher risk of a number of age-related con-
ditions and diseases including cardiovascular disease (CVD), hyperten-
sion, type 2 diabetes mellitus (T2DM), and cancer.4 Similarly, children
with obesity are at higher risk of these same diseases and conditions,
which were previously exclusively observed in adults. Children with
obesity have been shown to present with early onset of T2DM, hyper-
tension, CVD, and certain cancers or increased likelihood of disease
5
development in adulthood. Given that obesity shortens life expec-
tancy and that diseases and conditions associated with obesity are
similar to those seen in ageing, we propose that obesity is a disease
that accelerates ageing.
From the perspective of cell biology, obesity is associated with
240-bp shortened telomere length, corresponding to 8.8 years of age-
ing.6 Additionally, as estimated by all measures of epigenetic clocks,
obesity is linked to the acceleration of epigenetic age in different tis-
7
sues. Broadly speaking, obesity and ageing share a similar spectrum
of phenotypes—redox imbalance, mitochondrial dysfunction, accumu-
lation of macromolecules, weakened immunity, and systemic inflam-
mation. Thus, obesity possibly accelerates ageing at multiple levels
ranging from cells to systems. This review article aims to show how
obesity and ageing are “two sides of the same coin” through discussing
how obesity predisposes an individual to age-related conditions and
disease, and demonstrating how the mechanisms that perpetuate the
early-onset of chronic diseases in obesity parallel those of ageing.
2 | O B E S I T Y A N D LI F E E X P E C T A N C Y
Although there are several measures of adiposity in humans, the most
commonly used to classify obesity is body mass index (BMI = weight
[kg]/height [m]2). As BMI only considers weight and not body compo-
sition, the use of BMI is limited, especially for individuals with inter-
−2 8
mediate BMI ranges (ie, 20 to 29.9 kg
m ). Recreational and elite
athletes could be easily classified as overweight because of their high
lean mass without actually having excess adiposity.9,10 The variation
in body composition that accompanies assessment of weight by BMI
likely contributes to the variability observed in the association
between those classified as overweight and mortality. Some studies
have proposed that overweight is associated with excess
11,12
mortality, whereas others report no association or lower risk of
mortality.13 However, with some exceptions, BMI higher than
30 kg
m−2 has been reported to have excellent specificity and positive
predictive power for identifying obesity for both sexes.8 Studies con-
sistently showed that obesity reduces life expectancy markedly.3,11,12
Metrics such as percentage body fat,14 muscle mass index,15
waist-to-height ratio,16 waist-to-hip ratio,17 and android-gynoid fat
ratio18 have been shown to better diagnose obesity and assess and
predict total and cardiometabolic health, as they provide better infor-
mation about body composition and fat distribution. Although they
are better indicators of adiposity, studies establishing association
between many of these metrics and life expectancy are still limited.
More studies are needed to determine if the above metrics predict
mortality and life expectancy better than does BMI.
3 | OBESITY REINFORCES MACHINERY OF
AGEING
Ageing is a common feature of the life cycle of humans. It is charac-
terized by a progressive loss of physiological integrity, leading to
functional decline, and increased vulnerability to death.19 Besides
the onset of age-related diseases in senior adults, there are some
conserved ageing phenotypes in human and animals—redox imbal-
ance, mitochondrial dysfunction, increased apoptosis, cellular senes-
cence, insufficient autophagy, and increased inflammation
(Figure 1).20 Similar to ageing, obesity and excess calorie intake
appear to perpetuate the onset of age-related diseases through sim-
ilar mechanisms.
3.1 | Reactive oxygen species and redox
homeostasis
Reactive oxygen species (ROS) generated from normal cellular metab-
olism are largely produced in mitochondria. Through the Krebs cycle,
reducing equivalents such as NADH and FADH2 are produced and
transferred to the electron transport chain (ETC) where a transmem-
brane electrochemical proton gradient drives the synthesis of ATP.
Electrons being transferred along the ETC have sufficient free energy
to reduce molecular oxygen and inevitably produce ROS.
Well known functions of ROS are to oxidize DNA and lipid, alter
the activity of proteins, and damage cellular structures. More recently,
ROS have been demonstrated to be essential signalling molecules and
play important roles in maintaining homeostasis. Optimal levels of
ROS mediate neuroendocrine control of metabolism such as feeding
and energy expenditure,21 regulate normal vascular functions,22 and
support adipose tissue thermogenesis.23 Hydrogen peroxide, a key
ROS, inactivates phosphatases and is also responsible for redox modi-
fications, which change protein structure and function. The changes
result in ROS effecting a broad range of cellular events such as prolif-
eration, antioxidant gene activation, and DNA damage response.24 If
the production of ROS exceeds the antioxidant capacity and/or the
ability to handle ROS is impaired, redox imbalance occurs.
3.2 | Obesity induces a redox imbalance similar to
ageing
The presence of excess ROS in haematopoietic stem cell
(HSC), haematopoietic progenitor cell,25 skeletal muscle cells,26 and
adipocytes27 leads to excessive cellular damage and increases risk
TAM ET AL. 3

F I G U R E 1 Caloric excess increases the formation of reactive oxygen species (ROS) through the excess production of NADH and FADH2.
ROS causes damages to nucleus, endoplasmic reticulum (ER), and mitochondria. A, Impaired autophagy—overnutrition and obesity decrease
autophagic flux and impair fusion between autophagosomes and lysosomes. The reduced autophagy drastically decreases recycling of
malfunctioning endoplasmic reticulum, misfolded proteins, and damaged mitochondria. B, Compromised mitochondrial DNA (mtDNA) integrity—
ROS induces oxidative base lesions in mtDNA and results in mtDNA mutations. Defective mtDNA tends to be amplified preferentially within
cells. Therefore, damaged mtDNA will accumulate to detrimental levels in mitochondria, affecting normal functions of different cells. C, Enhanced
apoptosis—ROS generated in mitochondria activates p53 and the subsequent upregulation of pro-apoptotic genes such as Bax, Bak, and Puma.
Moreover, ROS-induced ER stress and irreparable damage cause the transfer of Ca2+ from ER to mitochondria, resulting in mitochondrial
membrane depolarization and the formation of Bax/Bak pores. The conformational change and oligomerization of Bax and Bak allow the
cytochrome c release into the cytosol, leading to the caspase activation cascades. The activation of effector caspases such as caspases-3, -6, and
-7 is responsible for the proteolytic cleavage of major structural proteins and the subsequent apoptosis. D, Mitochondrial damage-associated
molecular patterns (MiDAMPs)—the excessive generation of ROS can lead to destruction of mitochondria and cells. DAMPs such as mtDNA and
formyl peptide, if not properly degraded, will be released into the circulation. DAMPs activate NF-κB, which mediates the induction of a large
array of proinflammatory factors in macrophages. E, Senescence-associated secretory phenotypes (SASP)—the accumulation of DNA damage
results in the upregulation of p21, p16ink4a, and p53, which play important roles in DNA damage response (DDR). However, the chronic
activation of DDR and p53 leads to senescence growth arrest. The subsequent lamin B1 depletion in senescent cells causes large-scale chromatin
remodelling and alterations in gene expression. Chromatin modifications/factors such as H3K4me3, H3K9me2/3, H3K27me3, MacroH2A,
HMGA, and HP1 induce chromatin reorganization including both gain and loss of local interactions in heterochromatic regions. The formation of
condensed chromatin and the de-condensation of heterochromatin may cause packaging and silencing of proliferative genes and upregulation of
SASP genes, respectively, resulting in cellular senescence

of disease during ageing. Similarly, higher caloric consumption in
obesity is associated with oxidative stress due to an increase in
the generation of electrons from the ETC, increasing the formation
of ROS in tissues including adipose tissue, skeletal muscle, and
pancreas.28-31
The redox imbalance associated with obesity appears to induce
ageing in multiple cell types and tissues. In obesity, the excess pres-
ence of ROS has been shown to directly increase the expression of
the transcription factor Gfi1; this dysregulation changes the composi-
tion of the HSC compartment and dampens the function of HSC.32 Of
note, this ROS-induced dysregulation in HSC is strikingly similar to
33
other age-related haematological disorders. Another recent study
found that, in human bone marrow stromal cells, greater ROS concen-
trations in obesity enhanced insulin signalling by increasing the
abundance of insulin and leptin receptors.34 The subsequent increase
in oxidative phosphorylation of glucose lead to a redox imbalance
with ensuing stem cell exhaustion and accelerated bone marrow
micro-environment senescence conducive to bone fragility, which is
commonly observed in the aged population. Furthermore, excessive
ROS in obesity promotes changes in human adipose tissue that are
characteristic of ageing.35 Specifically, in obesity, chronically elevated
ROS inhibits healthy adipose expansion, promotes ectopic lipid accu-
mulation, and impairs insulin sensitivity through suppression of sterol
regulatory element binding transcription factor 1 (SREBF-1) in mouse
adipose tissue.36 Redox imbalance is not only limited to adipose tissue
but also occurs in endothelial cells and skeletal muscle.37 H2O2 gener-
ated from endothelial cells may diffuse to adjacent tissues, such as
skeletal muscle, to propagate ROS production through aquaporins.38
4 TAM ET AL.
The further propagation of ROS production by aquaporins may fur-
ther accelerate the ageing process in tissues.
3.3 | ROS formation induces mitochondrial
dysfunction and senescence-associated secretory
phenotype
With chronic ROS exposure, mitochondrial DNA (mtDNA) is damaged.
In human fibroblasts it has been shown that mtDNA damage is even
more extensive and persistent when compared to nuclear DNA
39
(nDNA) damage, as they are physically close to the ETC and not
protected by histones and chromatin.40 In general, uncontrolled for-
mation of ROS can induce rapid depolarization of the inner mitochon-
drial membrane potential compromising oxidative phosphorylation.
Moreover, the excess ROS may cause mutations in mtDNA, which
codes for proteins forming the oxidative phosphorylation system.
Dysfunctional mitochondria perpetuate inflammation, and affects the
function of multiple tissues predisposing individuals to age-related
conditions and diseases such as dementia, cardiomyopathy, and
diabetes.41
Of note, mtDNA is continuously recycled and generated in both
mitotic and postmitotic cells. Because of replicative segregation, dys-
functional mitochondria and healthy mitochondria are distributed
unequally in daughter cells. Moreover, defective mtDNA tends to be
preferentially amplified within cells. This phenomenon has been
suggested to be a compensatory mechanism for insufficient energy
production by defective mitochondria.42 Further evidence shows that
when human myocytes and hepatocytes with damaged mitochondria
are not eliminated, damage-associated molecular patterns (DAMPs)
including formyl peptides and non-methylated DNA are released into
circulation, triggering systemic inflammation.43
Size of mitochondria has been shown to decrease with age.44 Sim-
ilarly, obesity is associated with approximately 30% reduction of mito-
45
chondrial longitudinal and transverse area in human skeletal muscle,
suggesting the downregulation of mitochondrial biogenesis and
decreased mitochondrial content.46 It is possible that the reduction of
mitochondrial size in skeletal muscle is caused by impaired mitochon-
drial fusion, which is required for mtDNA stability and tolerance of
mtDNA mutations.47 Obesity also consistently reduces the expression
of PGC-1α, cytochrome c, and oxidative phosphorylation proteins in
skeletal muscle and adipose tissue of both animals and humans.48 It is
noteworthy that multiple factors contributing to obesity including
caloric excess and physical inactivity may contribute to the reduced
49
mitochondrial density in skeletal muscle. It is unlikely that the
reduced mitochondrial density is solely caused by obesity given the
fact that exercise is a major factor regulating mitochondrial biogene-
sis.50 Therefore, ageing, obesity, and/or sedentary behaviour can
impair mitochondrial fusion/fission and biogenesis and, hence, alter
the morphology and function of mitochondria.47
Dysfunctional mitochondria have also been shown to induce
mitochondrial dysfunction–associated senescence (MiDAS) in human
fibroblast, and mouse adipose tissue and skin. This mitochondria-
driven senescent state is characterized by low NAD+/NADH ratios,
which potently induces growth arrest and IL-1-independent
senescence-associated secretory phenotypes (SASPs) with strong
paracrine effects in vivo.51 Moreover, it is suggested that mitochon-
drial dysfunction could drive ageing phenotypes such as adipogenesis
inhibition and keratinocyte differentiation through a number of SASPs
including IL-10, CCL27, TNF-α, and HMGB1.
Uncontrolled formation of ROS further affects the cell cycle by
triggering deep senescence through tumour protein 53 (p53) activa-
tion, p16INK4a, and p21 expression, which potently downregulates
lamin B1 in the nuclei of primary human fibroblasts.52 Lamin B1 loss
has been identified as a pivotal event in triggering global and local
chromatin remodelling resulting in the production of proinflammatory
factors (eg, cytokines and chemokines), known as a part of the SASP.
The loss of repressive trimethylation of lysine 27 on histone H3
(H3K27me3) has also been associated with upregulated SASP
genes.53 Persistent SASP is known to promote cellular senescence,
chronic inflammation, and induce senescence in neighbouring cells
through paracrine signalling.54,55 Taken together, excessive ROS for-
mation, such as in obesity, triggers irreversible cellular senescence,
and induces chronic inflammation, which are key contributors to age-
related diseases.56
3.4 | Insufficient autophagy and apoptosis
As an evolutionarily conserved machinery for cellular recycling,
autophagy has been regarded as a promoter of longevity.57
Autophagy maintains intracellular organelle quality by catabolizing
cytosolic components to protect cells against stress. With obesity,
autophagic capacity is impaired, resulting in excessive accumulation of
malfunctioning organelles and misfolded proteins in various tissues.
Insulin resistance, endothelial dysfunction, and decline in cognitive
functions are conditions commonly associated with impaired
autophagy.58-60
Calorie restriction and physical exercise are known to activate
autophagy in different tissues and organs,60 while obesity inhibits
autophagy. mTOR is considered a major suppressor of autophagy.
Insulin and nutrients are well-known for activating mTOR through
Protein kinase B (Akt) signaling.61 Therefore, the hyperinsulinaemia
and/or hyperglycaemia that often accompanies obesity chronically
suppresses autophagy in skeletal muscle, adipose tissue, and liver
through the activation of mTOR and inhibition of forkhead box pro-
tein O transcription factor via Akt signaling.57,62
Mitophagy is an indispensable quality control mechanism con-
stantly removing damaged and dysfunctional mitochondria to main-
tain optimal function of different tissues in the body. Impaired
mitophagy in different tissues has been associated with frailty, cardio-
vascular, neurodegenerative, and metabolic diseases in obesity and
ageing.63,64 Recently, studies showed that impaired mitophagy is
linked to macrophage lineage, which is crucial to age-related changes
and chronic inflammation in obesity.65 Accumulation of damaged
mitochondria in macrophages due to insufficient mitophagy activates
TAM ET AL.
excessive secretion of IL-1β, which enhances macrophage death and
compromises macrophage-mediated immunity, tissue repair, and
healing.66 Mitochondrial ROS, mtDNA, and cardiolipin have been reg-
arded as the activators of NLRP3-inflammation. Antioxidant treat-
ment, reduction of mtDNA by ethidium bromide, inhibition of
mitochondrial protein synthesis by chloramphenicol, and increased
clearance of damaged mitochondria by p62 attenuate excessive IL-1β
release and prevents caspase-1 activation and subsequent cell death
in human macrophages.66 These findings collectively suggest that
unremoved damaged mitochondria, such as when mitophagy is
impaired in obesity, could possibly be major activators of chronic
inflammation and cell death.
IL-10 has been shown to promote mitophagy and eliminate ROS-
damaged mitochondria in macrophages through suppressing mTOR.
IL-10 drives the metabolic shift from glycolysis to oxidative phosphor-
ylation (OXPHOS) in macrophages. This glycolytic shift is crucial in
shaping the phenotypes of macrophages as OXPHOS is important for
M2 macrophage differentiation.67 Therefore, IL-10 is critical in con-
trolling the overall redox status and polarization of macrophages
through regulating autophagy. It is worth noting that low levels of IL-
10 has been associated with metabolic syndrome68, dyslipidaemia,69
and android obesity.70 In obesity, chronically activated mTOR may
perpetuate the already reduced autophagy by lowering circulating IL-
10, leading to the IL-1β–mediated inflammation and dysregulated
M1/M2 polarization in adipose tissue that is also commonly seen in
ageing.65,71
72
Besides inhibiting autophagy, it has been shown that obesity
and adipocyte-derived factors lead to endoplasmic reticulum
(ER) stress in hypothalamus, adipose tissue, liver, and skeletal and car-
diac muscle, typically associated with ageing.73 ER stress results in
74
misfolded proteins and dysfunctional mitochondria . Furthermore,
the ubiquitin-proteasome system, another mechanism degrading
misfolded proteins, is abnormally modulated in individuals with
obesity resulting in the aggregation of macromolecules in different
75
tissues. Both defective autophagy and proteasome dysfunction in
adipose tissue, liver, pancreas, and neurons have been proposed to
cause T2DM and Alzheimer disease (AD).76,77 Although protein
aggregates accumulate gradually with age, the obesity-induced
accumulation of damaged proteins, and obesity-inhibited autophagy
and ubiquitin proteasome system may speed up the cellular senes-
cence and premature apoptosis due to dysregulated protein
homeostasis.
Obesity and ageing have also been associated with apoptosis.
Oxidative stress due to obesity induces mtDNA lesions, mitochondrial
dysfunction, and increases cytochrome c levels and caspase 3 activity
in cytoplasm, leading to the activation of skeletal muscle apoptosis in
78
mice. Studies in mice have also shown that obesity-induced apopto-
sis can be observed in heart,79 liver,80 kidney,81 neurons,82 inner
ear,83 and photoreceptor cells in retina.84
Taken together, the evidence suggests that cellular senescence,
chronic inflammation, apoptosis, and functional declination in ageing
and obesity are, at least in part, mediated by redox imbalance, dys-
functional mitochondria, and insufficient autophagy.
5
4 | OBESITY DRIVES AGEING AT
M U L T I P L E L EV E L S
Accelerated ageing is commonly justified by the occurrence of charac-
teristic ageing phenotypes and biological features at an earlier age
than we normally observe.85 Some common cellular and molecular
alterations associated with ageing and obesity are listed in Figure 2.
These alterations lead to the upregulation of different SASP and
adipokines, which inhibit cellular maintenance pathways and enhance
the development of age-related diseases. Specifically, obesity acceler-
ates ageing by shortening telomere length, compromises the immune
system, and speeds up the early onset of age-related conditions
(Table 1). Moreover, obesity increases epigenetic ageing, a recent
approach to quantifying ageing.
4.1 | Telomere attrition
Telomeres are protective caps on the ends of chromosomes. Telo-
meres are several kilobase pairs of DNA having the sequence
TTAGGG. These telomeres are shortened by about 30 to 150 bp with
each cell division.106 For example, leukocyte telomere length of young
adults is about 8000 bp compared with about 7000 bp in the
elderly.107 When repair of critically short telomeres by telomerase
becomes impossible, apoptosis and cellular senescence are activated,
resulting in a functional decline in humans.108 Longer telomere length
has been associated with a lower risk of death.109
In addition to telomere shortening through normal cell division
and DNA replicative stress, obesity further enhances telomere short-
ening by inducing oxidative stress and accelerating the rate of telo-
mere erosion per replication. Telomeres in white blood cells have
been found to be 240-bp shorter in women with obesity vs normal-
weight women, corresponding to approximately eight more years of
ageing.6 This finding was supported by another study that showed
higher BMI and weight gain in adulthood between 30 and 39 years
old were associated with shorter telomere length in whole blood
cells.87 The effects of obesity on telomere length appear to affect all
ages, as compared with children without obesity; a study by Buxton
et al110 showed that children with obesity had 24% shorter leukocyte
telomere length, despite being 1 year younger.
Obesity accelerates the ageing of both subcutaneous and visceral
fat depots similarly. When compared with control patients, telomeres
in subcutaneous and visceral fat of patients with obesity were 28%
and 23% shorter, respectively.111 Although telomere shortening
appears to be the same for both fat depots, individuals with abdomi-
nal obesity are more prone to leukocyte telomere shortening.88
Another study consistently showed that visceral adipocyte size is neg-
atively associated with telomere length in visceral and subcutaneous
adipocytes.111
In obesity, shorter telomere length may be attributed not only to
greater adiposity but also to lower skeletal muscle as the two usually
go hand in hand. The Berlin Aging study found that leukocyte telo-
mere length was positively associated with leg lean mass even after
6 TAM ET AL.

F I G U R E 2 Both ageing and obesity are possible sources of age-related diseases via similar mechanisms. Chronic low-grade inflammation
associated with normal ageing drives the development of age-related diseases. Obesity also bolsters the onset of age-related diseases by
enhancing cellular ageing phenotypes and production of various cytokines and adipokines. Though different, there are similarities in the secretory
factors and molecular alterations of both ageing and obesity that creates a vicious propagatory cycle which promotes the development of age-
related diseases. Healthy diet, calorie restriction, and physical activity are proven to prevent obesity, and, for those who have developed obesity,
they may inhibit the vicious cycles by at least partially restoring normal cellular metabolism and inhibiting the secretion of a number of
proinflammatory factors and adipokines

adjusting for age, BMI, and C-reactive protein.112 Moreover, telomere
length is significantly shorter in men with sarcopenia compared with
those without.109
4.2 | Ageing of the immune system
Obesity during adolescence in mice leads to premature
immunosenescence during early adulthood.113 Interleukin profiles,
phagocytosis of macrophages, activity of natural killer cells, lympho-
cyte proliferation, and chemotaxis of macrophages and lymphocytes
113
are also impaired in adult animals with obesity. Inflammatory fac-
tors in plasma have been suggested to contribute to the premature
phenotypes of immunosenescence. A recent study showed that
plasma from patients with obesity induces apoptosis, dephosphoryla-
tion of γH2AX, and mitochondrial dysfunction in peripheral blood
mononuclear cells isolated from lean subjects,114 suggesting that
immunosenescence is sustained if the systemic inflammation is not
alleviated.
Obesity further decreases production of naïve T cell and acceler-
ates replacement of lymphostromal thymic zones with adipocytes,
90
which are considered phenotypes of thymic ageing. Obesity has
been demonstrated to accelerate ageing of the thymus by increased
apoptosis of newly generated thymocytes, and decreased T cell pre-
cursors and recent thymic emigrants. Visceral adiposity in particular
91
may be linked to T cell ageing. In mice, diet-induced visceral adipos-
ity causes the production of proinflammatory T cells (CD153+PD-
1+CD44hiCD4+). Similar to senescence-associated CD4+ T cells, these
CD153+PD-1+CD44hiCD4+ T cells induce proinflammatory cytokine
genes expression, and promote macrophage infiltration in visceral adi-
pose tissue (VAT).91 Similarly, obesity-induced metabolic stress trig-
gers preferential differentiation of CD4+ T cells into proinflammatory
T cells (CD44hiCCR7loCD62LloCXCR3+LFA1+) via phosphoinositide
3-kinase (PI3K) p110δ-Akt-dependent pathway.115 It is noteworthy
that senescence-associated beta-galactosidase (SA-β-gal), H2A his-
tone family member X (γ-H2AX), and p21 are upregulated and special
AT-rich sequence-binding protein-1 (Satb1) is downregulated in the
vast majority of these T cells, suggesting that obesity accelerates cel-
lular senescence in T cells.91 The effect of obesity on immune cell
senescence is not confined exclusively to T cells but also B cells. VAT
directly impairs B cell function by inducing differentiation of follicular
B cells into proinflammatory age-associated B cells.92 IL-21 and inter-
feron gamma (IFN-γ) have been suggested to contribute to this
differentiation.116
The effect of obesity on T cell senescence begs the question of
whether this effect is reversible. Diet-induced weight loss in mice suc-
cessfully decreased visceral fat mass but could not reverse the senes-
cence and proinflammatory properties of T cells, which are long-lived
and resistant to cell death.93 Thus, these prematurely senescent T
cells perpetuate chronic VAT inflammation. The irreversible senes-
cence of T cells may partially explain why lifestyle-induced weight loss
does not always correspond with reduced rates of cardiovascular
events in adults with overweight and obesity.117 Collectively, obesity
induces the ageing of the immune system by targeting different
immune cells, and the senescence of immune cells may not be
reversed by weight reduction.
TAM ET AL. 7

TABLE 1 Obesity accelerates ageing at multiple levels

Species and Tissue Key Measurements Major Findings Other Findings/Discussion

Telomere attrition
Men with obesity—midrectal
biopsy86
Human—whole blood87
Human—leukocyte88
Ageing of immune system
Human—thymus and T-cell89
Female mouse—thymus and
T-cell90
Mouse—T cell91
Male mouse—B cell92
Male mouse—T cell93
Telomere length
Telomere length
Telomere length
T-cell receptor excision circle
(TREC)
Thymic somatic index & naïve T
cells
Senescence-reminiscent T cells and
osteopontin
B cell functions assessed by
enzyme activation-induced
cytidine deaminase (AID)
expression
SA-β-gal and osteopontin
Weight reduction programme
increased telomere length (P =
.01)
• Baseline: ~239 bp
• Week 12: ~989 bp
• Week 52: ~2352 bp
Weight reduction programme
reduced DNA damage (measured
by a basic sites) by ~28% and
~48% at week 12 and 52 (P =
.02)
Mean telomere repeat copy
number to single-copy gene
copy number ratio:
• 1.33 in normal weight women
• 1.26 in women with overweight
or obesity
Waist-to-hip ratio is one of the
powerful predictors of telomere
shortening (odd ratio per 0.1
waist-to-hip increase = 1.4)
TREC was decreased by ~33% in
group with obesity and ~51% in
group with morbid obesity
Ageing
• decreased thymic somatic index
by ~50%
• decreased CD4+ and CD8+ naïve
T cells by ~79% and ~46%
Calorie restriction
• Increased thymic somatic index
by ~38%
• Increased CD4+ and CD8+ naïve
T cells by ~314% and ~93%
• Obesity increased
CD153+PD-1+CD4+
senescence-reminiscent cells by
~36 fold
• Obesity increased serum OPN by
~63%
• AID in LPS-stimulated splenic B
cells is negatively correlated with
the size of epididymal VAT (r =
-0.81, P = .0002)
HFD-induced obesity increased
• % of SA-β-gal positively stained
CD4 T cell by ~2.5 fold. 8 weeks
• Weight loss was associated with
increased telomere length and
reduced DNA damage in rectal
mucosa.
• Other nutritional impacts such as
levels of plasma lipids, insulin,
glucose, cholesterol, folate,
vitamin B12, homocysteine, and
CRP had no effects on telomere
length.
• There was no difference in
telomere length for subjects who
were on high-protein or
high-carbohydrate weight-loss
diets.
Weight gain since the 30s and
weight cycling were inversely
associated with telomere length.
Abdominal obesity has the
strongest effect on telomere
shortening after adjusting for
BMI, adipokines, and
inflammatory markers.
• Thymopoiesis in humans is
inversely related to BMI.
• Obesity constricts T-cell diversity
by accelerating age-related
thymic involution.
CR inhibited thymoadipogenesis by
targeting PPARγ pathway.
Transfer of
CD153+PD-1+CD44hiCD4+ T
cells into VAT of lean mice
induces key features of VAT
inflammation via OPN
upregulation.
Obesity accelerated B cell function
impairment in ageing mice by
promoting systemic
inflammation and increased
inflammatory B cell recruitment
into VAT.
Obesity induced senescence and
functional changes in T cells
which was linked to chronic
(Continues)
8 TAM ET AL.
TABLE 1 (Continued)
Species and Tissue
Age-related conditions
Male (Thy1)-h[A30P] AS TG
mouse*—neuron and life
span94
*These animals develop
age-dependent AS pathology
similar to human
Female Rat—brain95
Human—brain96
Male mouse—brain97
Young men—artery98
Key Measurements
Abundance of serine-129
phosphorylated α-synuclein (AS)
& life span
Morris water maze and
hippocampal synaptic function
Cerebral white-matter volume
Amyloidogenic deposits, β-amyloid
burden, and glial activation
Gross atherosclerotic lesions in the
right coronary artery (RCA), fatty
streaks, and AHA lesion grade in
the left anterior descending
coronary artery (LAD)
Major Findings
of normal diet reduced it by
~25%
• % of SA-β-gal positively stained
CD8 T cell by ~2.7 fold. 8 weeks
of normal diet reduced it by
~24%
• circulating osteopontin by ~65%.
8 weeks of normal diet reduced
it by ~11%
• HFD-induced obesity decreased
lifespan by ~20% (~20 months
vs ~16 months)
• HFD-induced obesity increased
Ser 129-p-αAS level by ~ 133%
(4 months of ageing increased
Ser 129-p-αAS level by 122%)
• HFD decreased dendritic spine
density by ~31% after 8 weeks
of HFD
• Ovariectomy further decreased
the dendritic spine density by
~21% compared with HFD
group
• HFD did not increase brain
mitochondrial ROS production
after 8 weeks of HFD, but
increased it by ~100% after 12
weeks of HFD
Individuals with obesity were
associated with brain atrophy
and this effect was found to be
strongest at the age of 40,
corresponding to an increase in
white matter-based brain age of
10 years.
HFD-induced obesity increased
• thio plaques by ~70%, ~30%,
~48%, and ~100%
• Β-amyloid deposits by ~50%,
~8%, ~34%, and ~73%
• microglial number by ~20%,
~35%, ~55%, and ~21%
in entorhinal cortex, subiculum,
CA1, and CA2/3 (hippocampal
subregions) of APOE4 animals.
No effects were seen in APOE3
animals.
Extent of fatty streaks (% of
surface area involved) increased
with BMI (P = .0001)
• BMI < 25: ~3.3%
• BMI = 25-30: ~5.2%
BMI > 30: ~7.1%
Other Findings/Discussion
inflammation in VAT. These
senescent T cells could not be
removed efficiently by weight
reduction, resulting in
self-sustaining chronic
inflammatory loop.
HFD-induced obesity accelerated
onset of terminal locomotor
phenotype accompanied by
earlier α-synucleinopathy and
astrogliosis which are associated
with ageing.
• HFD-induced obesity
accelerated cognitive
impairment by increasing
peripheral insulin resistance and
reducing hippocampal synaptic
plasticity. Oestrogen deprivation
could aggravate those
deleterious effects.
• The dendritic spine density
decreased before the increase in
brain mitochondrial ROS
production. The ROS may only
be responsible for the further
impairment of brain function but
not initiation of brain
dysfunction.
Excess adiposity has an adverse
impact on brain structure and
white-matter volume which are
highly related to ageing.
There was a significant interaction
between APOE4 and
diet-induced obesity
(gene-environment interaction)
on the risk of Alzheimer disease.
Obesity accelerated
AD-associated pathology in
APOE4 animals.
• Obesity accelerated the
age-related progression of
atherosclerosis decades before
clinical manifestations occur in
young men.
• Obesity is an important
modifiable factor contributing to
(Continues)
TAM ET AL. 9

TABLE 1 (Continued)

Species and Tissue Key Measurements Major Findings Other Findings/Discussion

Female rat—ovary99
Female mouse—skeletal muscle
and adipose tissue100
Human—skin101
Epigenetic ageing
Human—liver102
Human—blood103
Human—blood104
Number of primordial follicles and
atretic follicles
Physiological performance (activity,
gait, and rotarod) and lifespan
Stratum corneum hydration level,
transepidermal water loss, and
levels of advanced glycation
end-products
Epigenetic clock
Extrinsic epigenetic age
acceleration (EEAA) and intrinsic
epigenetic age acceleration
(IEAA)
Deviation of epigenetic age from
the calendar age (δAGE =
calendar age − epigenetic age)
Men with obesity had a higher
prevalence of
• AHA grades 2 to 3 (OR = 2.02,
95% CI = 1.08-3.78),
• AHA grades 4 to 5 (OR = 5.25,
95% CI = 2.12-12.98)
• stenosis >40% (OR = 2.35, 95%
CI = 1.16-4.76),
than those without obesity after
adjusting for other risk factors
HFD-induced obesity
• Decreased primordial follicles by
~48%
• Increased atretic follicles by
~24%
Calorie restriction
• Increased primordial follicles by
~24%
• Decreased atretic follicles by
~17%
Obesity accelerated the decline in
performance which is associated
with ageing
Obesity and diabetes
• decreased stratum corneum
hydration level by 19%
• increased transepidermal water
loss by 26% and levels of
advanced glycation
end-products by 15%
• Obesity increased epigenetic age
by 3.3 years for each 10 BMI
units
• Increased BMI is positively
associated with increased EEAA
(β = 0.4, P = .002) and IEAA (β =
0.22, P = .03)
• The association between δAGE
and change in BMI was
significant (r = -0.193, P = .009)
in a 25-year follow-up in
middle-aged individuals (40-49
years of age), suggesting that
increase in BMI accelerates
epigenetic ageing
development of coronary
atherosclerosis.
• Controlling childhood obesity is
important for long-range
prevention of age-related
chronic diseases.
HFD-induced obesity accelerated
ovarian follicle development and
rate of follicle loss through
activating mTOR and
downregulating SIRT1 pathway,
ultimately causing premature
ovarian failure.
Life-long obesity adversely
affected longevity and
physiological function. The
acceleration of ageing process is
associated with the levels of
oxidative stress.
Age-associated skin changes seen
in aged subjects can be seen in
patients with obesity and
diabetes in their 40s.
• Continuous excess calorie intake
induced oxidative stress and
metabolic pressure might point
to the mechanisms causing the
epigenetic ageing of liver.
• Bariatric surgery and rapid
weight loss could not reverse
the epigenetic ageing in liver
tissue.
The association between BMI and
IEAA was statistically significant
in both blood and liver, however,
the association established in
liver is much higher. It is possible
that different tissues have
different degrees of ageing.
BMI did not accelerate epigenetic
ageing in young adults (mean
age = 19.2 years), suggesting
that obesity-induced
acceleration of epigenetic age
takes place over time. The
effects of obesity may only be
(Continues)
10 TAM ET AL.

TABLE 1 (Continued)

Species and Tissue Key Measurements Major Findings Other Findings/Discussion

Mouse—liver105 Epigenetic age and ageing
signatures (methylome)
Reduction in epigenetic ages by
• Calorie restriction = 9.4 months
(P < 10−4)
• Rapamycin = 6 months (P < .05)
• Dwarfism = 10.1 months (P <
.01)
when compared with 22-month
old control mice
seen when the young adults
grow older.
148 CpG sites were used to
formulate the epigenetic clock
used in this study, in which 76
gained methylation with age and
the rest lost methylation with
age.

4.3 | Early onset of age-related conditions with obesity who are physically inactive are at an even greater risk of
developing mobility disability, further restricting daily activities.122,124
4.3.1 | Declines in cognition

Obesity is associated with age-related functional declines in the brain,
which are characterized by decreased executive functions, loss of
memory, and impaired processing speed.118 At the anatomical level,
results from the cortical reconstruction of 527 individuals have rev-
ealed that excess adiposity is associated with cerebral white-matter
atrophy corresponding to a 10-year older brain in people with obe-
sity.96 Obesity may accelerate the onset of neurodegenerative pheno-
types through the aggregation of α-synuclein, pathological protein
modifications, and neuroinflammation in mice.94 In humans,
α-synuclein also accumulates with age in brain; this accumulation not
only accelerates the onset of Parkinson disease but also interacts with
119
free fatty acid (FFA) in people with obesity and hyperlipidaemia.
women with low oestrogen levels, obesity has also been shown to
accelerate cognitive decline by increasing peripheral insulin resistance
and oxidative stress, leading to reduced hippocampal synaptic plastic-
95
ity in brain.
4.3.2 | Impaired mobility
Ageing decreases the functional capacity of older adults and increases
the risk of declines in mobility.120 Obesity is also associated with
declines in mobility. Contrary to popular belief, physically active peo-
ple with obesity appear to have an equally high risk of decreases in
mobility as inactive people with low adiposity.121 Moreover, people
with higher BMI were reported to have greater difficulties in per-
forming daily tasks, such as standing up from an armless chair, and
122
activities of daily living. A longitudinal study with a 46-year follow-
up showed that obesity at ages 30 to 49 years is associated with an
over two-fold increased risk of impaired mobility and activities of daily
living. Furthermore, men (women) with obesity were found to live 5.7
123
(5.02) fewer years free of mobility limitations. Another study dem-
onstrated that the relationship between BMI and subsequent physical
disability is curvilinear, increasing after a BMI 24 kg
m−2.124 People
4.3.3 | Hypertension
A recent study showed that over 60% of adults over 65 years have
hypertension, compared with about 20% for adults aged 35 to
44 years.125 The alterations in systolic and diastolic blood pressure
reflect stiffened blood vessels, decreased arterial compliance, and the
subsequent increase in pulse pressure with ageing.126 Similarly, indi-
viduals with obesity have higher vascular resistance. It is estimated
that over 60% of hypertension is directly attributable to adiposity.127
Excess adiposity increases the risk of developing hypertension by
increasing renal sodium retention through enhanced sympathetic tone,
In activation of the renin-angiotensin system, hyperinsulinaemia, struc-
tural changes in the kidneys, and elevation of circulating adipokines
such as leptin.128 As such, the prevalence of hypertension increases
significantly with increasing BMI categories in adults.129 Besides BMI,
the risk of hypertension has been shown to be up to 18 times higher in
young adult males with intra-abdominal fat area > 100 cm2.130 There-
fore, both BMI and central adiposity are critical factors for the devel-
opment of hypertension, a traditionally age-related condition.
Obesity is associated with hypertension not only in adults but
also in children. Eighty percent of the children with hypertension fall
above the 50th percentile in BMI, and nearly one-third of children
with hypertension fall above the 95th percentile in BMI.131 A study
involving 47 000 children showed that compared with those in the
lower BMI decile, children in the upper decile had a 2.5 to 3.7 time
greater risk of hypertension.132 BMI has also been shown to be the
factor most strongly associated with hypertension among all demo-
graphic and clinical factors analysed.131 Obesity-associated hyperten-
sion in childhood is a chronic medical condition predisposing children
and juveniles to early onset of age-related diseases, such as stroke
and ischaemic heart disease. On the other hand, it has been shown
that for every kilogramme of weight reduction, a decrease of 1.05 and
0.92 mmHg in systolic and diastolic blood pressure can be
obtained.133 Thus, not only does obesity increase the risk of
TAM ET AL.
hypertension; controlling body weight may be beneficial in reducing
this age-related condition.
4.4 | Epigenetic ageing
People with the same chronological age may not necessarily have the
same physiological age. Chronological age tells us how many calendar
days an individual has lived since birth. In contrast, physiological age,
or phenotypic age, is an ambiguous concept concerning the biological
age/state of the individual. Recently, epigenetic age has been used to
determine the impact of stresses on physiological ageing. Chronologi-
cal age and different stresses in life alter the methylation status in our
genome. Mathematical algorithms have been used to estimate the
DNA methylation age (or DNAm age) of a DNA source, which could
be tissues or organs. As DNAm age reflects both chronological and
physiological age, it indicates the physiological conditions of the tis-
sues or organs.
A study by Horvath et al102 showed that obesity accelerates epi-
genetic ageing of the liver in humans. New insight has been provided
by another study concluding that cumulative lifetime stress may
accelerate epigenetic ageing via glucocorticoid-induced methylation
134
in genomic DNA extracted from human whole blood. Coinciden-
tally, individuals with obesity have altered cortisol levels.135 Whether
the disturbed levels of cortisol and its metabolites would accelerate
epigenetic ageing via glucocorticoid-induced methylation needs fur-
ther investigation. Although lifetime stress, obesity, and normal age-
ing alter levels of methylation, the methylation sites are different and
trigger physiological ageing and functional declination in tissues or
organs via different mechanisms.136-138 However, if the genome-
wide methylation status of multiple CpG sites is considered, obesity,
ageing, and various stresses lead to a common outcome—epigenetic
ageing.
Notably, BMI is associated with epigenetic ageing in various tis-
sues, except in young adults. One of the possible explanations is
that obesity-accelerated epigenetic ageing takes place over a rela-
tively long period of time and young adults have not been exposed
to obesity long enough for noticeable alterations in epigenetic age-
104
ing to occur. To support the association between BMI and epige-
netic ageing, a longitudinal study has suggested that an increase in
BMI is associated with an increase in epigenetic age acceleration,103
although the correlations in liver are much more significant than
those in blood.
A recently emerged epigenetic biomarker of ageing, DNAm
PhenoAge, has been demonstrated to be a powerful predictor of
physical functioning, health span, cancers, AD, and all-cause mortal-
139
ity. Pathological characteristics of obesity including dysregulated
inflammation, increased DNA damage, and loss of proteostasis are
associated with DNAm PhenoAge.140 It is speculated that obesity
accelerates the DNAm PhenoAge through the above dysregulations
and, hence, induces the early onset of age-related diseases and func-
tional declines. One of the advantages of DNAm PhenoAge is that the
epigenetic age estimated from blood DNA is highly correlated with
11
most tissues in the human body. Thus, DNAm PhenoAge may be a
biomarker of physiological ageing, allowing us to estimate the level of
ageing as induced by obesity in different tissues in the future.
A study in bariatric surgery patients showed that noticeable
weight loss improved metabolic abnormalities in 21 subjects within a
9-month period.102 However, the surgery and significant weight loss
did not reverse epigenetic age acceleration in the liver. Thus, the
reversal of epigenetic age seems hard-won. In line with this specula-
tion, a previous study has shown that though exercise can induce
genome-wide changes in DNA methylation of adipose tissue, the
DNAm age of the adipose tissue is not affected.102,141 These observa-
tions are in agreement with those in the immune system, which
showed that weight loss could not reverse the senescence of T cells.
Although the reversal of epigenetic ageing is difficult, it has been pro-
posed that calorie restriction and dietary rapamycin can slow the epi-
genetic clock in mice livers.105
5 | OBESITY AND AGE-RELATED DISEASES
Age is a risk factor for a number of diseases. Improvements in life
expectancy increase the chance of acquiring age-related diseases. To
better illustrate our hypothesis that obesity is a disease that mirrors
ageing, Figure 3 shows the processes by which obesity contributes to
the development of age-related disease. In this section, we will focus
on how obesity increases disease burden and promotes the early
development of diseases that typically present in ageing. Some mech-
anisms by which obesity catalyses the development of these diseases
will also be examined.
5.1 | Influenza
Both people with obesity and older adults have greater susceptibility
to infection. Age has been well recognized as an independent risk fac-
tor for influenza and its complications; however, as a risk factor, obe-
sity receives much less attention. Following the 2009 H1N1 influenza
pandemic, several lines of evidence have supported obesity as a risk
factor for influenza.
A prospective hospital-based surveillance study showed that next
to age, obesity had the second highest odds ratio for risk of hospitali-
zation for influenza-associated severe acute respiratory illness.142 In
2009, more than 50% of Californians hospitalized with H1N1 infec-
tion had obesity.143 During flu season, compared with normal-weight
individuals, patients with class I and class II obesity have 1.45 and
2.12 times the risk of having respiratory hospitalization.144 According
to a global pooled analysis conducted by the World Health Organiza-
tion, the odds ratio for death given hospitalization for influenza
patients with BMI > 30 kg
m−2 was 2.9; moreover, the risk of death
for patients with BMI > 40 kg
m−2 was remarkably increased to
36.3.145 Similar findings can be obtained from another meta-analysis,
consisting of 59 studies, which showed that obesity increased the risk
of death and need for admission to hospital due to seasonal
12
influenza.146 Furthermore, obesity significantly increases the risk of
severe outcomes in children and teens (OR = 1.34), and adults (OR =
147
1.91). Compared to patients with normal body weight, patients
with obesity had prolonged time on mechanical ventilation (9.3 vs
6.5 days) and intensive care unit stays (13.7 vs 10.8 days).148 A review
focusing on pandemic influenza in the Southern Hemisphere also indi-
cated that influenza was more frequent and virulent in individuals
149
with obesity.
Immunization for influenza is the primary strategy for
preventing and reducing the severity of illness and its complica-
tions. In both obesity and ageing, the effectiveness of the influenza
vaccine is decreased. With ageing, the antibody response weakens
and decays faster because of reduced B cell production, defects in
isotype switching, and somatic hypermutation.150 The immune
response to influenza vaccination in obesity is also dampened. At
12 months post vaccination, higher BMI is associated with lower
151
antibody titers. Therefore, people with obesity are at higher risk
for influenza and less protected by vaccination. Of particular note
is that even when seroconversion or seroprotection rates are the
same, compared with lean adults, vaccinated adults with obesity
are still twice as likely to develop influenza and influenza-like
illness.152
5.2 | Sarcopenia
Sarcopenia is a muscular disease characterized by a progressive
decline in muscle mass and strength that increases the risk of
adverse outcomes including fall, fractures, physical disability, and
mortality.153 Although sarcopenia is often thought of as a disease
of ageing and is more common among older adults, sarcopenia can
occur earlier in life. With obesity, deleterious alterations in skeletal
muscle structure and metabolism may result in declines in muscle
mass and function.154
A common belief is that patients with obesity generate larger
muscular force because of the chronic overload stimulus on
weight-bearing muscles. However, the body-mass normalized
TAM ET AL.
F I G U R E 3 Many individuals with normal
weight (blue line) develop chronic diseases at
older ages, when they reach the threshold of
disease (the point of onset of a particular chronic
disease in an individual). However, people who are
overweight (purple line) or with obesity (brown
line) may reach the threshold of disease at a
younger age. In addition to promoting the early-
onset of chronic diseases, obesity also reduces the
healthy lifespan and shortens the total lifespan.
Unhealthy lifestyles, such as sedentary lifestyle
and cigarette smoking (red), may further increase
the likelihood of disease development and
severity of chronic diseases
muscular force of patients with obesity is weaker than that of indi-
viduals with healthy body weight.155 The smaller normalized mus-
cular force may be attributed to changes in muscle morphology.
Similar to ageing, obesity triggers the infiltration of fat into muscle,
which could be a cause of early development of sarcopenia as the
intramuscular lipid droplets hinder the regeneration potential and
function of skeletal muscle.156 Besides the muscular force, muscu-
lar endurance is negatively associated with BMI,157 which is also a
characteristic of sarcopenia.158 Taken together, patients with obe-
sity have been shown to have difficulty in performing activities of
daily living and are more at risk of falls and fractures,155 common
features of sarcopenia and ageing.
Sarcopenia is very likely to be exacerbated by obesity. This com-
bination of sarcopenia and obesity has recently been referred to as
sarcopenic obesity to reflect the fact that sarcopenia and obesity rein-
force themselves via a positive feedback mechanism.159 Besides acti-
vating the ubiquitin-proteasome system and apoptosis, obesity also
increases oxidative stress in skeletal muscle via elevated intracellular
generation of H2O2.160 Where adipose tissue is located may also
affect the level of muscular dysfunction. Recently, VAT hypertrophy
has been observed to cause muscle dysfunction through a dys-
regulated profile of adipokines.161 IL-6 and IL-1β secreted by visceral
adipocytes downregulate expression of contractile proteins in
myotubes, resulting in an abnormal distribution of muscle fibre size.
Interestingly, subcutaneous fat does not appear to induce muscle
wasting to the same extent as visceral fat. Consistently, the increase
in visceral and not total fat mass upregulated ubiquitin ligase, muscle
RING-finger protein-1 (MuRF-1), caspase-3, and poly-ADP-ribose
polymerase cleavage in muscle of rats with obesity.162 Collectively,
obesity is associated with muscle loss and impaired muscle metabo-
lism, which are some common features of ageing.
5.3 | Type 2 diabetes mellitus
Older adults represent a large portion of new diabetes incidence.163
In the United States, close to one in three adults over the age of
TAM ET AL.
65 years have T2DM. Ninety percent of people with T2DM have
overweight or obesity,164 and the presence of obesity accelerates the
development of T2DM.165,166 Children with T2DM were rarely
reported in the 1980s.167 As the incidence of obesity in children
climbed over the past 30 years, so too did the prevalence of
T2DM.168 It is estimated that, compared to those with a normal BMI,
the incidence of T2DM is four times higher in children with obe-
166
sity. Moreover, BMI changes the lifetime risk of T2DM. At age
18, the lifetime risks of T2DM are 7.6% for those with a BMI of
18.5 kg
m−2, whereas those with a BMI > 35 kg
m−2 have a lifetime
169
risk of 70.3%. Childhood and adolescent obesity have been associ-
ated with increased risk of obesity and diabetes in adulthood. While
the development of obesity in adulthood increases T2DM risk by five
fold, persistent obesity from childhood increases the risk of T2DM by
170
12 fold. People who are overweight in childhood and become lean
in adulthood may also have a higher chance of acquiring insulin resis-
tance and impaired glucose metabolism, putting them at risk of
T2DM.171
It is noteworthy that some children with obesity and diabetes
could be glutamic acid decarboxylase (GAD) and/or Protein Tyro-
sine Phosphatase, Receptor Type N (IA-2) positive,169 which is a
characteristic of islet autoimmunity contributing to insulin defi-
ciency, making these children pathologically closer to their normal-
weight counterparts with type 1 diabetes (T1DM).172 Moreover,
abdominal obesity may further impair β-cell function via pancreatic
ER stress.173 A recent study has shown that hyperglycaemia and
hyperinsulinaemia induce accelerated ageing of β cells. 174
Either
biological ageing or obesity-induced ageing would reduce replica-
tive capacity of β cells, resulting in a larger population of old and
senescent cells in islets.174 Proinflammatory cytokines associated
with obesity may lead to β cell death through impaired mitochon-
173,175
dria and ER stress. Therefore, obesity could possibly make
T2DM closer to T1DM because of insulin deficiency, which is also
commonly seen in older adults.176
Glucose intolerance due to peripheral insulin resistance and insuf-
ficient β cell function have been shown to be a part of ageing,
predisposing older individuals to T2DM.177,178 In both obesity and
ageing, insulin resistance is associated with the accumulation of intra-
179,180
myocellular lipid. Although some studies do not find that long-
chain acyl CoA and ceramides are mediators of insulin resistance,
others show that accumulation of fatty acid metabolites (eg, long-
chain acyl coenzyme A, diacylglycerol [DAG], and ceramides) in obe-
181
sity induce insulin resistance in skeletal muscle. DAG may trigger
muscle insulin resistance through inhibiting insulin-mediated glucose
transport activity and decreasing insulin receptor substrate 1 (IRS-1)-
related PI3K signalling.182,183 Moreover, obesity partially impairs the
insulin signaling in liver by relaxing its inhibition of gluconeogenesis
and maintaining the activation of lipogenesis through the differential
expression of IRS-1 and IRS-2 in periportal and perivenous zones of
liver.184 In obesity and ageing, the peripheral insulin resistance,
ectopic fat accumulation in skeletal muscle, and β cell dysfunction
impair the functions of the corresponding organs and, together, drive
the development of T2DM.
13
5.4 | Cardiovascular disease
Atherosclerosis is a pathological condition underlying CVD in which
lipids accumulate at susceptible sites in the major conduit arteries.185
The identification of calcified plaque in ancient mummies suggests
that atherosclerosis is a common phenotype of normal human age-
ing.186 However, obesity at an early age accelerates this ageing pro-
cess decades before it manifests clinically.98 The greater risk of CVD
in obesity are well established, and thus, the discussion here is
brief.187-189 Compared with normal-weight individuals, even those
with metabolically healthy obesity have been shown to have a higher
chance of developing coronary heart disease (HR = 1.49) and heart
failure (HR = 1.96).190 Collectively, abdominal obesity may be a strong
catalyst in promoting the early onset of CVD.191 A meta-analysis of
82 000 subjects in nine cohort studies showed that a one SD higher
waist-to-hip ratio and waist circumference increased the risk of CVD
mortality by 15%.192 Children who exceed the 75th percentile of
waist circumference and waist-to-height ratio have significantly higher
values for CVD risk factors including blood pressure, total cholesterol,
low-density lipoprotein cholesterol (LDL-C), and lower high-density
lipoprotein cholesterol (HDL-C).193
Excess adiposity dysregulates production of hormones, which
subsequently leads to systemic inflammation and impaired metabolism
in the body. Adipose tissue is now well established as an endocrine
organ secreting a variety of factors, such as leptin, adiponectin, IL-6,
MCP-1, TNF-α, and plasminogen activator inhibitor-1 (PAI-1), which
contribute to hyperaggregability, hypercoagulability, hypofibrinolysis,
and accelerates the progression of arterial ageing, as well as, the
development of atherosclerosis.194 For the detailed mechanisms
linking obesity with CVD, readers are referred to previous
studies.194,195
5.5 | Alzheimer's disease
AD is an irreversible neurological disorder characterized by a decline
in cognition and progressive loss of self-care ability. It is well-known
that age is the most determining factor for the development of
AD,196 affecting approximately 11% of people older than 65 years
and approximately 32% of people older than 85 years.197 It is spec-
ulated that obesity accelerates the onset of AD. A systematic
review of 580 000 participants in 19 cohorts showed that mid-life
obesity increases the risk of dementia including AD and vascular
dementia at older ages. Individuals aged between 35 and 65 with
BMI ≥ 30 kg
m−2 have a 23% to 47% higher risk of dementia.198 A
longitudinal study with a 14-year follow-up has demonstrated that
mid-life adiposity is associated with β-amyloid burden, accelerated
brain atrophy, and neurodegeneration, accelerating the clinical
course of AD.199 This study also showed that every unit increase in
mid-life BMI advances the onset of AD by 6.7 months. Oppositely,
the onset of AD can be delayed by a healthy mid-life BMI profile.
Recently, a number of interactions between genetic variation and
obesity have been identified. ApoE4 (ε4 allele of apolipoprotein E) has
14
been suggested to interact with obesity to increase the risk of AD.200
Diet-induced obesity in mice affects apoE4, leading to an acceleration
of AD-related pathology by increasing β-amyloid accumulation, a hall-
mark of AD.97 Another study focusing on non–diet-induced obesity
has revealed that the obesity-related gene (FTO) interacts with apoE4
and may increase the risk for AD by approximately 300%.201 A partial
explanation for this interaction is that the greater appetite and higher
fat intake in FTO occur simultaneously with the inefficient removal of
lipid content in circulation caused by apoE4.202,203 The combined
effects appear to lead to the predisposition of early-onset AD in car-
204,205
riers of these alleles with obesity. Another mechanism by which
obesity may increases the risk of AD is through alterations in leptin
and inflammatory signalling in the central nervous system, which
increase food intake, accumulation of β-amyloid, and microvascular
206-208
disease.
5.6 | Cancer
As one ages, numerous cell divisions result in an increase in the accu-
mulation of harmful mutations, which can ultimately evolve into dis-
eases such as cancer.209 According to the United States Cancer
210
Statistics, compared with those aged between 40 and 44, the inci-
dence of cancer in those over 70 years is about eight times higher.
Statistics from Cancer Research UK show the same trend, with half of
all cancers affecting patients over the age of 70.211 It is suggested that
intrinsic risk factors (eg, age) only contributes 10% to 30% to cancer
development, while extrinsic risk factors (eg, obesity) contribute to
the rest of cancer development.212
Epidemiological studies indicated that 35% of cancers can be
213
attributed to dietary factors and obesity. These studies revealed
that excess adiposity increases the relative risk of cancers 1.1 to 7.1
times, including (in the order of increasing relative risk) thyroid, breast,
ovary, gallbladder, colon and rectum, pancreas, meningioma, multiple
myeloma, kidney, liver, gastric cardia, esophagus, and corpus
uteri.214-221 Oppositely, every 10% of weight lost has been associated
with a 10% risk reduction of all cancers.222 Interestingly, the benefits
of weight reduction in females seem to be more promising. Bariatric
surgery has been associated with 44% risk reduction of endometrial
cancer.223 Furthermore, weight loss of 5 kg or more after age 18 has
been shown to reduce risk of postmenopausal breast cancer.224 Col-
lectively, though cancer has traditionally been associated with ageing,
there is strong evidence showing that obesity is associated with
higher risk of cancers and the absence of excess body fat reduces the
risk of cancers.
Obesity could fuel the initiation, progression, and metastasis of
cancer through pathways that parallel ageing including ROS genera-
tion, inflammation, and altered molecular signalling in cancer cells. In
addition to mutations that accumulate steadily through normal ageing,
obesity may induce additional mutations through genotoxic sub-
28,225,226
stances and, hence, accelerate the onset of cancer. Obesity-
associated metabolites, such as 8-oxo-20 -deoxyguanosine,
4-hydroxynonenal and 16α-hydroxyestrone, have been suggested to
TAM ET AL.
promote genome instability and cancer development. Besides
destabilizing the human genome and inducing mutations, metabolic
dysregulation that results from excess adiposity may fuel the growth
of cancer cells.227,228
Recently, multiple studies have shown that cancer cells with
increased expression of fatty acid receptor, CD36, are able to initiate
metastasis and promote self-renewal.229-231 It is particularly notewor-
thy that omental adipocytes are able to induce expression of CD36 in
ovarian cancer.232 We speculate that central obesity would increase
the risk of intra-abdominal tumours as the excess omental fat is likely
to increase the direct transfer of lipids from adipocytes to cancer
cells.232 High-fat diet also increases metastatic potential of CD36+
cancer cells. CD36+ cancer cells acquire energy from β-oxidation of
fatty acids enabling self-survival at sites far away from the primary
tumour.229 Collectively, increased adiposity and adipocyte-associated
soluble factors could reprogram tumour metabolism so that the
expression of CD36 matches the external supplies of FFA and choles-
terol, allowing cancer cells to flexibly adapt to the tumour micro-
environment.
In obesity, the dysfunctional adipose tissue is known to activate
multiple pathways that support cell proliferation, cell survival, inva-
sion, metastasis, and angiogenesis in cancer.233 SASP has also been
demonstrated to play a crucial role in promoting obesity-associated
hepatocellular carcinoma in mice. Obesity alters gut microbiota and,
hence, increases production of deoxycholic acid (DCA), which causes
DNA damages through redox imbalance.234 The elevated DCA
induces cellular senescence and provokes SASP in hepatic stellate
cells, which in turn produce proinflammatory factors to promote the
development of hepatocellular carcinoma. Therefore, not only does
obesity alter the adipokine profiles in individuals with excess adipos-
ity, it may also cause cellular senescence in stellate cells, inducing
senescence secretomes that promote tumourigenesis and cancer
development.
6 | CONC LU SIONS
In this review, we show that obesity and ageing are “two sides of the
same coin” by demonstrating how the pathology of obesity parallels
those of ageing at multiple levels from the molecular to systemic. At
the molecular level, both obesity and ageing promote cellular senes-
cence, inflammation, and mitochondrial dysfunction through redox
imbalance and insufficient autophagy. The accumulation of
malfunctioning mitochondria in obesity leads to chronic inflammation
that reinforces the senescence-associated secretory phenotypes of
ageing. The inhibition of autophagy in obesity results in further aggre-
gation of misfolded proteins, which are common features of ageing.
Moreover, the attrition of telomeres, which is characteristic of ageing,
is also observed in obesity. Another indicator of ageing, the epigenetic
clock, is also accelerated in obesity. These molecular and cellular
changes that are subsequent to both obesity and ageing have a pro-
found impact on human health, hastening the development of age-
related conditions and diseases.
TAM ET AL.
Similar to ageing, obesity has been associated with a weakened
immune system, declines in cognition, impaired mobility, and
hypertension. Obesity also increases the susceptibility to infection, as
those with obesity have been shown to be more susceptible to influ-
enza and its symptoms, and are less protected with vaccination. Fur-
thermore, not only does obesity increase the risk of age-related
diseases including T2DM, sarcopenia, AD, and cancer, obesity does so
through mechanisms that are common to ageing.
Recent advances show that obesity is associated with profound
alterations in the gut microbiota235 and blood metabolome.236 For
instance, obesity is associated with reduced level of bilirubin, which
is an antioxidizing and anti-inflammatory metabolite.237,238 It is
speculated that specific bacterial populations are responsible for
the increased catabolism of bilirubin in individuals with obesity.238
Future research should examine how obesity accelerates ageing
through the disturbance of the connection between microbiota and
the metabolome.
Altogether, the evidence collectively indicates that obesity is a
disease that accelerates ageing. Viewing obesity as an ageing disease
may allow us to better understand and develop more effective
treatment strategies for obesity.
ACKNOWLEDGEMEN T
B.T.T. is supported by the Horizon Postdoctoral Fellowship. S.S. holds
a Canada Research Chair (Tier 2) in Clinical Nutrition.
CONF LICT OF IN TE RE ST
No conflict of interest was declared.
ORCID
Bjorn T. Tam https://orcid.org/0000-0001-6740-8674
Jose A. Morais https://orcid.org/0000-0001-9366-6626
Sylvia Santosa https://orcid.org/0000-0001-5814-6086
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