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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 ratio18 have been shown to better diagnose obesity and assess and
predict total and cardiometabolic health, as they provide better infor-
1
Obesity increases the risk of premature death by 1.45 to 2.76 fold mation about body composition and fat distribution. Although they
and shortens lifespan by up to 20 years.2,3 We hypothesize that the are better indicators of adiposity, studies establishing association
shorter life expectancy observed in obesity is partially attributable to between many of these metrics and life expectancy are still limited.
the fact that obesity accelerates ageing, as conditions and com- More studies are needed to determine if the above metrics predict
orbidities of obesity mirror those of ageing and age-related diseases. mortality and life expectancy better than does BMI.
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 3 | OBESITY REINFORCES MACHINERY OF
with obesity are at higher risk of these same diseases and conditions, AGEING
which were previously exclusively observed in adults. Children with
obesity have been shown to present with early onset of T2DM, hyper- Ageing is a common feature of the life cycle of humans. It is charac-
tension, CVD, and certain cancers or increased likelihood of disease terized by a progressive loss of physiological integrity, leading to
5
development in adulthood. Given that obesity shortens life expec- functional decline, and increased vulnerability to death.19 Besides
tancy and that diseases and conditions associated with obesity are the onset of age-related diseases in senior adults, there are some
similar to those seen in ageing, we propose that obesity is a disease conserved ageing phenotypes in human and animals—redox imbal-
that accelerates ageing. ance, mitochondrial dysfunction, increased apoptosis, cellular senes-
From the perspective of cell biology, obesity is associated with cence, insufficient autophagy, and increased inflammation
240-bp shortened telomere length, corresponding to 8.8 years of age- (Figure 1).20 Similar to ageing, obesity and excess calorie intake
ing.6 Additionally, as estimated by all measures of epigenetic clocks, appear to perpetuate the onset of age-related diseases through sim-
obesity is linked to the acceleration of epigenetic age in different tis- ilar mechanisms.
7
sues. Broadly speaking, obesity and ageing share a similar spectrum
of phenotypes—redox imbalance, mitochondrial dysfunction, accumu- 3.1 | Reactive oxygen species and redox
lation of macromolecules, weakened immunity, and systemic inflam- homeostasis
mation. Thus, obesity possibly accelerates ageing at multiple levels
ranging from cells to systems. This review article aims to show how Reactive oxygen species (ROS) generated from normal cellular metab-
obesity and ageing are “two sides of the same coin” through discussing olism are largely produced in mitochondria. Through the Krebs cycle,
how obesity predisposes an individual to age-related conditions and reducing equivalents such as NADH and FADH2 are produced and
disease, and demonstrating how the mechanisms that perpetuate the transferred to the electron transport chain (ETC) where a transmem-
early-onset of chronic diseases in obesity parallel those of ageing. 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.
2 | O B E S I T Y A N D LI F E E X P E C T A N C Y Well known functions of ROS are to oxidize DNA and lipid, alter
the activity of proteins, and damage cellular structures. More recently,
Although there are several measures of adiposity in humans, the most ROS have been demonstrated to be essential signalling molecules and
commonly used to classify obesity is body mass index (BMI = weight play important roles in maintaining homeostasis. Optimal levels of
[kg]/height [m]2). As BMI only considers weight and not body compo- ROS mediate neuroendocrine control of metabolism such as feeding
sition, the use of BMI is limited, especially for individuals with inter- and energy expenditure,21 regulate normal vascular functions,22 and
−2 8
mediate BMI ranges (ie, 20 to 29.9 kgm ). Recreational and elite support adipose tissue thermogenesis.23 Hydrogen peroxide, a key
athletes could be easily classified as overweight because of their high ROS, inactivates phosphatases and is also responsible for redox modi-
lean mass without actually having excess adiposity.9,10 The variation fications, which change protein structure and function. The changes
in body composition that accompanies assessment of weight by BMI result in ROS effecting a broad range of cellular events such as prolif-
likely contributes to the variability observed in the association eration, antioxidant gene activation, and DNA damage response.24 If
between those classified as overweight and mortality. Some studies the production of ROS exceeds the antioxidant capacity and/or the
have proposed that overweight is associated with excess ability to handle ROS is impaired, redox imbalance occurs.
11,12
mortality, whereas others report no association or lower risk of
mortality.13 However, with some exceptions, BMI higher than 3.2 | Obesity induces a redox imbalance similar to
30 kgm−2 has been reported to have excellent specificity and positive ageing
predictive power for identifying obesity for both sexes.8 Studies con-
sistently showed that obesity reduces life expectancy markedly.3,11,12 The presence of excess ROS in haematopoietic stem cell
Metrics such as percentage body fat,14 muscle mass index,15 (HSC), haematopoietic progenitor cell,25 skeletal muscle cells,26 and
waist-to-height ratio,16 waist-to-hip ratio,17 and android-gynoid fat 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 abundance of insulin and leptin receptors.34 The subsequent increase
obesity is associated with oxidative stress due to an increase in in oxidative phosphorylation of glucose lead to a redox imbalance
the generation of electrons from the ETC, increasing the formation with ensuing stem cell exhaustion and accelerated bone marrow
of ROS in tissues including adipose tissue, skeletal muscle, and micro-environment senescence conducive to bone fragility, which is
pancreas.28-31 commonly observed in the aged population. Furthermore, excessive
The redox imbalance associated with obesity appears to induce ROS in obesity promotes changes in human adipose tissue that are
ageing in multiple cell types and tissues. In obesity, the excess pres- characteristic of ageing.35 Specifically, in obesity, chronically elevated
ence of ROS has been shown to directly increase the expression of ROS inhibits healthy adipose expansion, promotes ectopic lipid accu-
the transcription factor Gfi1; this dysregulation changes the composi- mulation, and impairs insulin sensitivity through suppression of sterol
tion of the HSC compartment and dampens the function of HSC.32 Of regulatory element binding transcription factor 1 (SREBF-1) in mouse
note, this ROS-induced dysregulation in HSC is strikingly similar to adipose tissue.36 Redox imbalance is not only limited to adipose tissue
33
other age-related haematological disorders. Another recent study but also occurs in endothelial cells and skeletal muscle.37 H2O2 gener-
found that, in human bone marrow stromal cells, greater ROS concen- ated from endothelial cells may diffuse to adjacent tissues, such as
trations in obesity enhanced insulin signalling by increasing the skeletal muscle, to propagate ROS production through aquaporins.38
4 TAM ET AL.

The further propagation of ROS production by aquaporins may fur- driven senescent state is characterized by low NAD+/NADH ratios,
ther accelerate the ageing process in tissues. 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-
3.3 | ROS formation induces mitochondrial drial dysfunction could drive ageing phenotypes such as adipogenesis
dysfunction and senescence-associated secretory inhibition and keratinocyte differentiation through a number of SASPs
phenotype including IL-10, CCL27, TNF-α, and HMGB1.
Uncontrolled formation of ROS further affects the cell cycle by
With chronic ROS exposure, mitochondrial DNA (mtDNA) is damaged. triggering deep senescence through tumour protein 53 (p53) activa-
In human fibroblasts it has been shown that mtDNA damage is even tion, p16INK4a, and p21 expression, which potently downregulates
more extensive and persistent when compared to nuclear DNA lamin B1 in the nuclei of primary human fibroblasts.52 Lamin B1 loss
39
(nDNA) damage, as they are physically close to the ETC and not has been identified as a pivotal event in triggering global and local
protected by histones and chromatin.40 In general, uncontrolled for- chromatin remodelling resulting in the production of proinflammatory
mation of ROS can induce rapid depolarization of the inner mitochon- factors (eg, cytokines and chemokines), known as a part of the SASP.
drial membrane potential compromising oxidative phosphorylation. The loss of repressive trimethylation of lysine 27 on histone H3
Moreover, the excess ROS may cause mutations in mtDNA, which (H3K27me3) has also been associated with upregulated SASP
codes for proteins forming the oxidative phosphorylation system. genes.53 Persistent SASP is known to promote cellular senescence,
Dysfunctional mitochondria perpetuate inflammation, and affects the chronic inflammation, and induce senescence in neighbouring cells
function of multiple tissues predisposing individuals to age-related through paracrine signalling.54,55 Taken together, excessive ROS for-
conditions and diseases such as dementia, cardiomyopathy, and mation, such as in obesity, triggers irreversible cellular senescence,
diabetes.41 and induces chronic inflammation, which are key contributors to age-
Of note, mtDNA is continuously recycled and generated in both related diseases.56
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 3.4 | Insufficient autophagy and apoptosis
preferentially amplified within cells. This phenomenon has been
suggested to be a compensatory mechanism for insufficient energy As an evolutionarily conserved machinery for cellular recycling,
production by defective mitochondria.42 Further evidence shows that autophagy has been regarded as a promoter of longevity.57
when human myocytes and hepatocytes with damaged mitochondria Autophagy maintains intracellular organelle quality by catabolizing
are not eliminated, damage-associated molecular patterns (DAMPs) cytosolic components to protect cells against stress. With obesity,
including formyl peptides and non-methylated DNA are released into autophagic capacity is impaired, resulting in excessive accumulation of
circulation, triggering systemic inflammation.43 malfunctioning organelles and misfolded proteins in various tissues.
Size of mitochondria has been shown to decrease with age.44 Sim- Insulin resistance, endothelial dysfunction, and decline in cognitive
ilarly, obesity is associated with approximately 30% reduction of mito- functions are conditions commonly associated with impaired
45
chondrial longitudinal and transverse area in human skeletal muscle, autophagy.58-60
suggesting the downregulation of mitochondrial biogenesis and Calorie restriction and physical exercise are known to activate
decreased mitochondrial content.46 It is possible that the reduction of autophagy in different tissues and organs,60 while obesity inhibits
mitochondrial size in skeletal muscle is caused by impaired mitochon- autophagy. mTOR is considered a major suppressor of autophagy.
drial fusion, which is required for mtDNA stability and tolerance of Insulin and nutrients are well-known for activating mTOR through
mtDNA mutations.47 Obesity also consistently reduces the expression Protein kinase B (Akt) signaling.61 Therefore, the hyperinsulinaemia
of PGC-1α, cytochrome c, and oxidative phosphorylation proteins in and/or hyperglycaemia that often accompanies obesity chronically
skeletal muscle and adipose tissue of both animals and humans.48 It is suppresses autophagy in skeletal muscle, adipose tissue, and liver
noteworthy that multiple factors contributing to obesity including through the activation of mTOR and inhibition of forkhead box pro-
caloric excess and physical inactivity may contribute to the reduced tein O transcription factor via Akt signaling.57,62
49
mitochondrial density in skeletal muscle. It is unlikely that the Mitophagy is an indispensable quality control mechanism con-
reduced mitochondrial density is solely caused by obesity given the stantly removing damaged and dysfunctional mitochondria to main-
fact that exercise is a major factor regulating mitochondrial biogene- tain optimal function of different tissues in the body. Impaired
sis.50 Therefore, ageing, obesity, and/or sedentary behaviour can mitophagy in different tissues has been associated with frailty, cardio-
impair mitochondrial fusion/fission and biogenesis and, hence, alter vascular, neurodegenerative, and metabolic diseases in obesity and
the morphology and function of mitochondria.47 ageing.63,64 Recently, studies showed that impaired mitophagy is
Dysfunctional mitochondria have also been shown to induce linked to macrophage lineage, which is crucial to age-related changes
mitochondrial dysfunction–associated senescence (MiDAS) in human and chronic inflammation in obesity.65 Accumulation of damaged
fibroblast, and mouse adipose tissue and skin. This mitochondria- mitochondria in macrophages due to insufficient mitophagy activates
TAM ET AL. 5

excessive secretion of IL-1β, which enhances macrophage death and 4 | OBESITY DRIVES AGEING AT
compromises macrophage-mediated immunity, tissue repair, and M U L T I P L E L EV E L S
healing.66 Mitochondrial ROS, mtDNA, and cardiolipin have been reg-
arded as the activators of NLRP3-inflammation. Antioxidant treat- Accelerated ageing is commonly justified by the occurrence of charac-
ment, reduction of mtDNA by ethidium bromide, inhibition of teristic ageing phenotypes and biological features at an earlier age
mitochondrial protein synthesis by chloramphenicol, and increased than we normally observe.85 Some common cellular and molecular
clearance of damaged mitochondria by p62 attenuate excessive IL-1β alterations associated with ageing and obesity are listed in Figure 2.
release and prevents caspase-1 activation and subsequent cell death These alterations lead to the upregulation of different SASP and
in human macrophages.66 These findings collectively suggest that adipokines, which inhibit cellular maintenance pathways and enhance
unremoved damaged mitochondria, such as when mitophagy is the development of age-related diseases. Specifically, obesity acceler-
impaired in obesity, could possibly be major activators of chronic ates ageing by shortening telomere length, compromises the immune
inflammation and cell death. system, and speeds up the early onset of age-related conditions
IL-10 has been shown to promote mitophagy and eliminate ROS- (Table 1). Moreover, obesity increases epigenetic ageing, a recent
damaged mitochondria in macrophages through suppressing mTOR. approach to quantifying ageing.
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 4.1 | Telomere attrition
M2 macrophage differentiation.67 Therefore, IL-10 is critical in con-
trolling the overall redox status and polarization of macrophages Telomeres are protective caps on the ends of chromosomes. Telo-
through regulating autophagy. It is worth noting that low levels of IL- meres are several kilobase pairs of DNA having the sequence
10 has been associated with metabolic syndrome68, dyslipidaemia,69 TTAGGG. These telomeres are shortened by about 30 to 150 bp with
and android obesity.70 In obesity, chronically activated mTOR may each cell division.106 For example, leukocyte telomere length of young
perpetuate the already reduced autophagy by lowering circulating IL- adults is about 8000 bp compared with about 7000 bp in the
10, leading to the IL-1β–mediated inflammation and dysregulated elderly.107 When repair of critically short telomeres by telomerase
M1/M2 polarization in adipose tissue that is also commonly seen in becomes impossible, apoptosis and cellular senescence are activated,
ageing.65,71 resulting in a functional decline in humans.108 Longer telomere length
72
Besides inhibiting autophagy, it has been shown that obesity has been associated with a lower risk of death.109
and adipocyte-derived factors lead to endoplasmic reticulum In addition to telomere shortening through normal cell division
(ER) stress in hypothalamus, adipose tissue, liver, and skeletal and car- and DNA replicative stress, obesity further enhances telomere short-
diac muscle, typically associated with ageing.73 ER stress results in ening by inducing oxidative stress and accelerating the rate of telo-
74
misfolded proteins and dysfunctional mitochondria . Furthermore, mere erosion per replication. Telomeres in white blood cells have
the ubiquitin-proteasome system, another mechanism degrading been found to be 240-bp shorter in women with obesity vs normal-
misfolded proteins, is abnormally modulated in individuals with weight women, corresponding to approximately eight more years of
obesity resulting in the aggregation of macromolecules in different ageing.6 This finding was supported by another study that showed
75
tissues. Both defective autophagy and proteasome dysfunction in higher BMI and weight gain in adulthood between 30 and 39 years
adipose tissue, liver, pancreas, and neurons have been proposed to old were associated with shorter telomere length in whole blood
cause T2DM and Alzheimer disease (AD).76,77 Although protein cells.87 The effects of obesity on telomere length appear to affect all
aggregates accumulate gradually with age, the obesity-induced ages, as compared with children without obesity; a study by Buxton
accumulation of damaged proteins, and obesity-inhibited autophagy et al110 showed that children with obesity had 24% shorter leukocyte
and ubiquitin proteasome system may speed up the cellular senes- telomere length, despite being 1 year younger.
cence and premature apoptosis due to dysregulated protein Obesity accelerates the ageing of both subcutaneous and visceral
homeostasis. fat depots similarly. When compared with control patients, telomeres
Obesity and ageing have also been associated with apoptosis. in subcutaneous and visceral fat of patients with obesity were 28%
Oxidative stress due to obesity induces mtDNA lesions, mitochondrial and 23% shorter, respectively.111 Although telomere shortening
dysfunction, and increases cytochrome c levels and caspase 3 activity appears to be the same for both fat depots, individuals with abdomi-
in cytoplasm, leading to the activation of skeletal muscle apoptosis in nal obesity are more prone to leukocyte telomere shortening.88
78
mice. Studies in mice have also shown that obesity-induced apopto- Another study consistently showed that visceral adipocyte size is neg-
sis can be observed in heart,79 liver,80 kidney,81 neurons,82 inner atively associated with telomere length in visceral and subcutaneous
ear,83 and photoreceptor cells in retina.84 adipocytes.111
Taken together, the evidence suggests that cellular senescence, In obesity, shorter telomere length may be attributed not only to
chronic inflammation, apoptosis, and functional declination in ageing greater adiposity but also to lower skeletal muscle as the two usually
and obesity are, at least in part, mediated by redox imbalance, dys- go hand in hand. The Berlin Aging study found that leukocyte telo-
functional mitochondria, and insufficient autophagy. 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 CD153+PD-1+CD44hiCD4+ T cells induce proinflammatory cytokine
length is significantly shorter in men with sarcopenia compared with genes expression, and promote macrophage infiltration in visceral adi-
those without.109 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
4.2 | Ageing of the immune system 3-kinase (PI3K) p110δ-Akt-dependent pathway.115 It is noteworthy
that senescence-associated beta-galactosidase (SA-β-gal), H2A his-
Obesity during adolescence in mice leads to premature tone family member X (γ-H2AX), and p21 are upregulated and special
immunosenescence during early adulthood.113 Interleukin profiles, AT-rich sequence-binding protein-1 (Satb1) is downregulated in the
phagocytosis of macrophages, activity of natural killer cells, lympho- vast majority of these T cells, suggesting that obesity accelerates cel-
cyte proliferation, and chemotaxis of macrophages and lymphocytes lular senescence in T cells.91 The effect of obesity on immune cell
113
are also impaired in adult animals with obesity. Inflammatory fac- senescence is not confined exclusively to T cells but also B cells. VAT
tors in plasma have been suggested to contribute to the premature directly impairs B cell function by inducing differentiation of follicular
phenotypes of immunosenescence. A recent study showed that B cells into proinflammatory age-associated B cells.92 IL-21 and inter-
plasma from patients with obesity induces apoptosis, dephosphoryla- feron gamma (IFN-γ) have been suggested to contribute to this
tion of γH2AX, and mitochondrial dysfunction in peripheral blood differentiation.116
mononuclear cells isolated from lean subjects,114 suggesting that The effect of obesity on T cell senescence begs the question of
immunosenescence is sustained if the systemic inflammation is not whether this effect is reversible. Diet-induced weight loss in mice suc-
alleviated. cessfully decreased visceral fat mass but could not reverse the senes-
Obesity further decreases production of naïve T cell and acceler- cence and proinflammatory properties of T cells, which are long-lived
ates replacement of lymphostromal thymic zones with adipocytes, and resistant to cell death.93 Thus, these prematurely senescent T
90
which are considered phenotypes of thymic ageing. Obesity has cells perpetuate chronic VAT inflammation. The irreversible senes-
been demonstrated to accelerate ageing of the thymus by increased cence of T cells may partially explain why lifestyle-induced weight loss
apoptosis of newly generated thymocytes, and decreased T cell pre- does not always correspond with reduced rates of cardiovascular
cursors and recent thymic emigrants. Visceral adiposity in particular events in adults with overweight and obesity.117 Collectively, obesity
91
may be linked to T cell ageing. In mice, diet-induced visceral adipos- induces the ageing of the immune system by targeting different
ity causes the production of proinflammatory T cells (CD153+PD- immune cells, and the senescence of immune cells may not be
1+CD44hiCD4+). Similar to senescence-associated CD4+ T cells, these 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 Telomere length Weight reduction programme • Weight loss was associated with
biopsy86 increased telomere length (P = increased telomere length and
.01) reduced DNA damage in rectal
• Baseline: ~239 bp mucosa.
• Week 12: ~989 bp • Other nutritional impacts such as
• Week 52: ~2352 bp levels of plasma lipids, insulin,
Weight reduction programme glucose, cholesterol, folate,
reduced DNA damage (measured vitamin B12, homocysteine, and
by a basic sites) by ~28% and CRP had no effects on telomere
~48% at week 12 and 52 (P = length.
.02) • There was no difference in
telomere length for subjects who
were on high-protein or
high-carbohydrate weight-loss
diets.
Human—whole blood87 Telomere length Mean telomere repeat copy Weight gain since the 30s and
number to single-copy gene weight cycling were inversely
copy number ratio: associated with telomere length.
• 1.33 in normal weight women
• 1.26 in women with overweight
or obesity
Human—leukocyte88 Telomere length Waist-to-hip ratio is one of the Abdominal obesity has the
powerful predictors of telomere strongest effect on telomere
shortening (odd ratio per 0.1 shortening after adjusting for
waist-to-hip increase = 1.4) BMI, adipokines, and
inflammatory markers.
Ageing of immune system
Human—thymus and T-cell89 T-cell receptor excision circle TREC was decreased by ~33% in • Thymopoiesis in humans is
(TREC) group with obesity and ~51% in inversely related to BMI.
group with morbid obesity • Obesity constricts T-cell diversity
by accelerating age-related
thymic involution.
Female mouse—thymus and Thymic somatic index & naïve T Ageing CR inhibited thymoadipogenesis by
T-cell90 cells • decreased thymic somatic index targeting PPARγ pathway.
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%
Mouse—T cell91 Senescence-reminiscent T cells and • Obesity increased Transfer of
osteopontin CD153+PD-1+CD4+ CD153+PD-1+CD44hiCD4+ T
senescence-reminiscent cells by cells into VAT of lean mice
~36 fold induces key features of VAT
• Obesity increased serum OPN by inflammation via OPN
~63% upregulation.
Male mouse—B cell92 B cell functions assessed by • AID in LPS-stimulated splenic B Obesity accelerated B cell function
enzyme activation-induced cells is negatively correlated with impairment in ageing mice by
cytidine deaminase (AID) the size of epididymal VAT (r = promoting systemic
expression -0.81, P = .0002) inflammation and increased
inflammatory B cell recruitment
into VAT.
Male mouse—T cell93 SA-β-gal and osteopontin HFD-induced obesity increased Obesity induced senescence and
• % of SA-β-gal positively stained functional changes in T cells
CD4 T cell by ~2.5 fold. 8 weeks which was linked to chronic
(Continues)
8 TAM ET AL.

TABLE 1 (Continued)

Species and Tissue Key Measurements Major Findings Other Findings/Discussion


of normal diet reduced it by inflammation in VAT. These
~25% senescent T cells could not be
• % of SA-β-gal positively stained removed efficiently by weight
CD8 T cell by ~2.7 fold. 8 weeks reduction, resulting in
of normal diet reduced it by self-sustaining chronic
~24% inflammatory loop.
• circulating osteopontin by ~65%.
8 weeks of normal diet reduced
it by ~11%
Age-related conditions
Male (Thy1)-h[A30P] AS TG Abundance of serine-129 • HFD-induced obesity decreased HFD-induced obesity accelerated
mouse*—neuron and life phosphorylated α-synuclein (AS) lifespan by ~20% (~20 months onset of terminal locomotor
span94 & life span vs ~16 months) phenotype accompanied by
*These animals develop • HFD-induced obesity increased earlier α-synucleinopathy and
age-dependent AS pathology Ser 129-p-αAS level by ~ 133% astrogliosis which are associated
similar to human (4 months of ageing increased with ageing.
Ser 129-p-αAS level by 122%)
Female Rat—brain95 Morris water maze and • HFD decreased dendritic spine • HFD-induced obesity
hippocampal synaptic function density by ~31% after 8 weeks accelerated cognitive
of HFD impairment by increasing
• Ovariectomy further decreased peripheral insulin resistance and
the dendritic spine density by reducing hippocampal synaptic
~21% compared with HFD plasticity. Oestrogen deprivation
group could aggravate those
• HFD did not increase brain deleterious effects.
mitochondrial ROS production • The dendritic spine density
after 8 weeks of HFD, but decreased before the increase in
increased it by ~100% after 12 brain mitochondrial ROS
weeks of HFD production. The ROS may only
be responsible for the further
impairment of brain function but
not initiation of brain
dysfunction.
Human—brain96 Cerebral white-matter volume Individuals with obesity were Excess adiposity has an adverse
associated with brain atrophy impact on brain structure and
and this effect was found to be white-matter volume which are
strongest at the age of 40, highly related to ageing.
corresponding to an increase in
white matter-based brain age of
10 years.
Male mouse—brain97 Amyloidogenic deposits, β-amyloid HFD-induced obesity increased There was a significant interaction
burden, and glial activation • thio plaques by ~70%, ~30%, between APOE4 and
~48%, and ~100% diet-induced obesity
• Β-amyloid deposits by ~50%, (gene-environment interaction)
~8%, ~34%, and ~73% on the risk of Alzheimer disease.
• microglial number by ~20%, Obesity accelerated
~35%, ~55%, and ~21% AD-associated pathology in
in entorhinal cortex, subiculum, APOE4 animals.
CA1, and CA2/3 (hippocampal
subregions) of APOE4 animals.
No effects were seen in APOE3
animals.
Young men—artery98 Gross atherosclerotic lesions in the Extent of fatty streaks (% of • Obesity accelerated the
right coronary artery (RCA), fatty surface area involved) increased age-related progression of
streaks, and AHA lesion grade in with BMI (P = .0001) atherosclerosis decades before
the left anterior descending • BMI < 25: ~3.3% clinical manifestations occur in
coronary artery (LAD) • BMI = 25-30: ~5.2% young men.
BMI > 30: ~7.1% • 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


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

TABLE 1 (Continued)

Species and Tissue Key Measurements Major Findings Other Findings/Discussion


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

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, 4.3.3 | Hypertension
which are characterized by decreased executive functions, loss of
memory, and impaired processing speed.118 At the anatomical level, A recent study showed that over 60% of adults over 65 years have
results from the cortical reconstruction of 527 individuals have rev- hypertension, compared with about 20% for adults aged 35 to
ealed that excess adiposity is associated with cerebral white-matter 44 years.125 The alterations in systolic and diastolic blood pressure
atrophy corresponding to a 10-year older brain in people with obe- reflect stiffened blood vessels, decreased arterial compliance, and the
sity.96 Obesity may accelerate the onset of neurodegenerative pheno- subsequent increase in pulse pressure with ageing.126 Similarly, indi-
types through the aggregation of α-synuclein, pathological protein viduals with obesity have higher vascular resistance. It is estimated
modifications, and neuroinflammation in mice.94 In humans, that over 60% of hypertension is directly attributable to adiposity.127
α-synuclein also accumulates with age in brain; this accumulation not Excess adiposity increases the risk of developing hypertension by
only accelerates the onset of Parkinson disease but also interacts with increasing renal sodium retention through enhanced sympathetic tone,
119
free fatty acid (FFA) in people with obesity and hyperlipidaemia. In activation of the renin-angiotensin system, hyperinsulinaemia, struc-
women with low oestrogen levels, obesity has also been shown to tural changes in the kidneys, and elevation of circulating adipokines
accelerate cognitive decline by increasing peripheral insulin resistance such as leptin.128 As such, the prevalence of hypertension increases
and oxidative stress, leading to reduced hippocampal synaptic plastic- significantly with increasing BMI categories in adults.129 Besides BMI,
95
ity in brain. 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-
4.3.2 | Impaired mobility opment of hypertension, a traditionally age-related condition.
Obesity is associated with hypertension not only in adults but
Ageing decreases the functional capacity of older adults and increases also in children. Eighty percent of the children with hypertension fall
the risk of declines in mobility.120 Obesity is also associated with above the 50th percentile in BMI, and nearly one-third of children
declines in mobility. Contrary to popular belief, physically active peo- with hypertension fall above the 95th percentile in BMI.131 A study
ple with obesity appear to have an equally high risk of decreases in involving 47 000 children showed that compared with those in the
mobility as inactive people with low adiposity.121 Moreover, people lower BMI decile, children in the upper decile had a 2.5 to 3.7 time
with higher BMI were reported to have greater difficulties in per- greater risk of hypertension.132 BMI has also been shown to be the
forming daily tasks, such as standing up from an armless chair, and factor most strongly associated with hypertension among all demo-
122
activities of daily living. A longitudinal study with a 46-year follow- graphic and clinical factors analysed.131 Obesity-associated hyperten-
up showed that obesity at ages 30 to 49 years is associated with an sion in childhood is a chronic medical condition predisposing children
over two-fold increased risk of impaired mobility and activities of daily and juveniles to early onset of age-related diseases, such as stroke
living. Furthermore, men (women) with obesity were found to live 5.7 and ischaemic heart disease. On the other hand, it has been shown
123
(5.02) fewer years free of mobility limitations. Another study dem- that for every kilogramme of weight reduction, a decrease of 1.05 and
onstrated that the relationship between BMI and subsequent physical 0.92 mmHg in systolic and diastolic blood pressure can be
disability is curvilinear, increasing after a BMI 24 kgm−2.124 People obtained.133 Thus, not only does obesity increase the risk of
TAM ET AL. 11

hypertension; controlling body weight may be beneficial in reducing most tissues in the human body. Thus, DNAm PhenoAge may be a
this age-related condition. 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
4.4 | Epigenetic ageing weight loss improved metabolic abnormalities in 21 subjects within a
9-month period.102 However, the surgery and significant weight loss
People with the same chronological age may not necessarily have the did not reverse epigenetic age acceleration in the liver. Thus, the
same physiological age. Chronological age tells us how many calendar reversal of epigenetic age seems hard-won. In line with this specula-
days an individual has lived since birth. In contrast, physiological age, tion, a previous study has shown that though exercise can induce
or phenotypic age, is an ambiguous concept concerning the biological genome-wide changes in DNA methylation of adipose tissue, the
age/state of the individual. Recently, epigenetic age has been used to DNAm age of the adipose tissue is not affected.102,141 These observa-
determine the impact of stresses on physiological ageing. Chronologi- tions are in agreement with those in the immune system, which
cal age and different stresses in life alter the methylation status in our showed that weight loss could not reverse the senescence of T cells.
genome. Mathematical algorithms have been used to estimate the Although the reversal of epigenetic ageing is difficult, it has been pro-
DNA methylation age (or DNAm age) of a DNA source, which could posed that calorie restriction and dietary rapamycin can slow the epi-
be tissues or organs. As DNAm age reflects both chronological and genetic clock in mice livers.105
physiological age, it indicates the physiological conditions of the tis-
sues or organs.
A study by Horvath et al102 showed that obesity accelerates epi- 5 | OBESITY AND AGE-RELATED DISEASES
genetic ageing of the liver in humans. New insight has been provided
by another study concluding that cumulative lifetime stress may Age is a risk factor for a number of diseases. Improvements in life
accelerate epigenetic ageing via glucocorticoid-induced methylation expectancy increase the chance of acquiring age-related diseases. To
134
in genomic DNA extracted from human whole blood. Coinciden- better illustrate our hypothesis that obesity is a disease that mirrors
tally, individuals with obesity have altered cortisol levels.135 Whether ageing, Figure 3 shows the processes by which obesity contributes to
the disturbed levels of cortisol and its metabolites would accelerate the development of age-related disease. In this section, we will focus
epigenetic ageing via glucocorticoid-induced methylation needs fur- on how obesity increases disease burden and promotes the early
ther investigation. Although lifetime stress, obesity, and normal age- development of diseases that typically present in ageing. Some mech-
ing alter levels of methylation, the methylation sites are different and anisms by which obesity catalyses the development of these diseases
trigger physiological ageing and functional declination in tissues or will also be examined.
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 5.1 | Influenza
ageing.
Notably, BMI is associated with epigenetic ageing in various tis- Both people with obesity and older adults have greater susceptibility
sues, except in young adults. One of the possible explanations is to infection. Age has been well recognized as an independent risk fac-
that obesity-accelerated epigenetic ageing takes place over a rela- tor for influenza and its complications; however, as a risk factor, obe-
tively long period of time and young adults have not been exposed sity receives much less attention. Following the 2009 H1N1 influenza
to obesity long enough for noticeable alterations in epigenetic age- pandemic, several lines of evidence have supported obesity as a risk
104
ing to occur. To support the association between BMI and epige- factor for influenza.
netic ageing, a longitudinal study has suggested that an increase in A prospective hospital-based surveillance study showed that next
BMI is associated with an increase in epigenetic age acceleration,103 to age, obesity had the second highest odds ratio for risk of hospitali-
although the correlations in liver are much more significant than zation for influenza-associated severe acute respiratory illness.142 In
those in blood. 2009, more than 50% of Californians hospitalized with H1N1 infec-
A recently emerged epigenetic biomarker of ageing, DNAm tion had obesity.143 During flu season, compared with normal-weight
PhenoAge, has been demonstrated to be a powerful predictor of individuals, patients with class I and class II obesity have 1.45 and
physical functioning, health span, cancers, AD, and all-cause mortal- 2.12 times the risk of having respiratory hospitalization.144 According
139
ity. Pathological characteristics of obesity including dysregulated to a global pooled analysis conducted by the World Health Organiza-
inflammation, increased DNA damage, and loss of proteostasis are tion, the odds ratio for death given hospitalization for influenza
associated with DNAm PhenoAge.140 It is speculated that obesity patients with BMI > 30 kgm−2 was 2.9; moreover, the risk of death
accelerates the DNAm PhenoAge through the above dysregulations for patients with BMI > 40 kgm−2 was remarkably increased to
and, hence, induces the early onset of age-related diseases and func- 36.3.145 Similar findings can be obtained from another meta-analysis,
tional declines. One of the advantages of DNAm PhenoAge is that the consisting of 59 studies, which showed that obesity increased the risk
epigenetic age estimated from blood DNA is highly correlated with of death and need for admission to hospital due to seasonal
12 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

influenza.146 Furthermore, obesity significantly increases the risk of muscular force of patients with obesity is weaker than that of indi-
severe outcomes in children and teens (OR = 1.34), and adults (OR = viduals with healthy body weight.155 The smaller normalized mus-
147
1.91). Compared to patients with normal body weight, patients cular force may be attributed to changes in muscle morphology.
with obesity had prolonged time on mechanical ventilation (9.3 vs Similar to ageing, obesity triggers the infiltration of fat into muscle,
6.5 days) and intensive care unit stays (13.7 vs 10.8 days).148 A review which could be a cause of early development of sarcopenia as the
focusing on pandemic influenza in the Southern Hemisphere also indi- intramuscular lipid droplets hinder the regeneration potential and
cated that influenza was more frequent and virulent in individuals function of skeletal muscle.156 Besides the muscular force, muscu-
149
with obesity. lar endurance is negatively associated with BMI,157 which is also a
Immunization for influenza is the primary strategy for characteristic of sarcopenia.158 Taken together, patients with obe-
preventing and reducing the severity of illness and its complica- sity have been shown to have difficulty in performing activities of
tions. In both obesity and ageing, the effectiveness of the influenza daily living and are more at risk of falls and fractures,155 common
vaccine is decreased. With ageing, the antibody response weakens features of sarcopenia and ageing.
and decays faster because of reduced B cell production, defects in Sarcopenia is very likely to be exacerbated by obesity. This com-
isotype switching, and somatic hypermutation.150 The immune bination of sarcopenia and obesity has recently been referred to as
response to influenza vaccination in obesity is also dampened. At sarcopenic obesity to reflect the fact that sarcopenia and obesity rein-
12 months post vaccination, higher BMI is associated with lower force themselves via a positive feedback mechanism.159 Besides acti-
151
antibody titers. Therefore, people with obesity are at higher risk vating the ubiquitin-proteasome system and apoptosis, obesity also
for influenza and less protected by vaccination. Of particular note increases oxidative stress in skeletal muscle via elevated intracellular
is that even when seroconversion or seroprotection rates are the generation of H2O2.160 Where adipose tissue is located may also
same, compared with lean adults, vaccinated adults with obesity affect the level of muscular dysfunction. Recently, VAT hypertrophy
are still twice as likely to develop influenza and influenza-like has been observed to cause muscle dysfunction through a dys-
illness.152 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.
5.2 | Sarcopenia Interestingly, subcutaneous fat does not appear to induce muscle
wasting to the same extent as visceral fat. Consistently, the increase
Sarcopenia is a muscular disease characterized by a progressive in visceral and not total fat mass upregulated ubiquitin ligase, muscle
decline in muscle mass and strength that increases the risk of RING-finger protein-1 (MuRF-1), caspase-3, and poly-ADP-ribose
adverse outcomes including fall, fractures, physical disability, and polymerase cleavage in muscle of rats with obesity.162 Collectively,
mortality.153 Although sarcopenia is often thought of as a disease obesity is associated with muscle loss and impaired muscle metabo-
of ageing and is more common among older adults, sarcopenia can lism, which are some common features of ageing.
occur earlier in life. With obesity, deleterious alterations in skeletal
muscle structure and metabolism may result in declines in muscle
mass and function.154 5.3 | Type 2 diabetes mellitus
A common belief is that patients with obesity generate larger
muscular force because of the chronic overload stimulus on Older adults represent a large portion of new diabetes incidence.163
weight-bearing muscles. However, the body-mass normalized In the United States, close to one in three adults over the age of
TAM ET AL. 13

65 years have T2DM. Ninety percent of people with T2DM have 5.4 | Cardiovascular disease
overweight or obesity,164 and the presence of obesity accelerates the
development of T2DM.165,166 Children with T2DM were rarely Atherosclerosis is a pathological condition underlying CVD in which
reported in the 1980s.167 As the incidence of obesity in children lipids accumulate at susceptible sites in the major conduit arteries.185
climbed over the past 30 years, so too did the prevalence of The identification of calcified plaque in ancient mummies suggests
T2DM.168 It is estimated that, compared to those with a normal BMI, that atherosclerosis is a common phenotype of normal human age-
the incidence of T2DM is four times higher in children with obe- ing.186 However, obesity at an early age accelerates this ageing pro-
166
sity. Moreover, BMI changes the lifetime risk of T2DM. At age cess decades before it manifests clinically.98 The greater risk of CVD
18, the lifetime risks of T2DM are 7.6% for those with a BMI of in obesity are well established, and thus, the discussion here is
18.5 kgm−2, whereas those with a BMI > 35 kgm−2 have a lifetime brief.187-189 Compared with normal-weight individuals, even those
169
risk of 70.3%. Childhood and adolescent obesity have been associ- with metabolically healthy obesity have been shown to have a higher
ated with increased risk of obesity and diabetes in adulthood. While chance of developing coronary heart disease (HR = 1.49) and heart
the development of obesity in adulthood increases T2DM risk by five failure (HR = 1.96).190 Collectively, abdominal obesity may be a strong
fold, persistent obesity from childhood increases the risk of T2DM by catalyst in promoting the early onset of CVD.191 A meta-analysis of
170
12 fold. People who are overweight in childhood and become lean 82 000 subjects in nine cohort studies showed that a one SD higher
in adulthood may also have a higher chance of acquiring insulin resis- waist-to-hip ratio and waist circumference increased the risk of CVD
tance and impaired glucose metabolism, putting them at risk of mortality by 15%.192 Children who exceed the 75th percentile of
T2DM.171 waist circumference and waist-to-height ratio have significantly higher
It is noteworthy that some children with obesity and diabetes values for CVD risk factors including blood pressure, total cholesterol,
could be glutamic acid decarboxylase (GAD) and/or Protein Tyro- low-density lipoprotein cholesterol (LDL-C), and lower high-density
sine Phosphatase, Receptor Type N (IA-2) positive,169 which is a lipoprotein cholesterol (HDL-C).193
characteristic of islet autoimmunity contributing to insulin defi- Excess adiposity dysregulates production of hormones, which
ciency, making these children pathologically closer to their normal- subsequently leads to systemic inflammation and impaired metabolism
weight counterparts with type 1 diabetes (T1DM).172 Moreover, in the body. Adipose tissue is now well established as an endocrine
abdominal obesity may further impair β-cell function via pancreatic organ secreting a variety of factors, such as leptin, adiponectin, IL-6,
ER stress.173 A recent study has shown that hyperglycaemia and MCP-1, TNF-α, and plasminogen activator inhibitor-1 (PAI-1), which
hyperinsulinaemia induce accelerated ageing of β cells. 174
Either contribute to hyperaggregability, hypercoagulability, hypofibrinolysis,
biological ageing or obesity-induced ageing would reduce replica- and accelerates the progression of arterial ageing, as well as, the
tive capacity of β cells, resulting in a larger population of old and development of atherosclerosis.194 For the detailed mechanisms
senescent cells in islets.174 Proinflammatory cytokines associated linking obesity with CVD, readers are referred to previous
with obesity may lead to β cell death through impaired mitochon- studies.194,195
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 5.5 | Alzheimer's disease
Glucose intolerance due to peripheral insulin resistance and insuf-
ficient β cell function have been shown to be a part of ageing, AD is an irreversible neurological disorder characterized by a decline
predisposing older individuals to T2DM.177,178 In both obesity and in cognition and progressive loss of self-care ability. It is well-known
ageing, insulin resistance is associated with the accumulation of intra- that age is the most determining factor for the development of
179,180
myocellular lipid. Although some studies do not find that long- AD,196 affecting approximately 11% of people older than 65 years
chain acyl CoA and ceramides are mediators of insulin resistance, and approximately 32% of people older than 85 years.197 It is spec-
others show that accumulation of fatty acid metabolites (eg, long- ulated that obesity accelerates the onset of AD. A systematic
chain acyl coenzyme A, diacylglycerol [DAG], and ceramides) in obe- review of 580 000 participants in 19 cohorts showed that mid-life
181
sity induce insulin resistance in skeletal muscle. DAG may trigger obesity increases the risk of dementia including AD and vascular
muscle insulin resistance through inhibiting insulin-mediated glucose dementia at older ages. Individuals aged between 35 and 65 with
transport activity and decreasing insulin receptor substrate 1 (IRS-1)- BMI ≥ 30 kgm−2 have a 23% to 47% higher risk of dementia.198 A
related PI3K signalling.182,183 Moreover, obesity partially impairs the longitudinal study with a 14-year follow-up has demonstrated that
insulin signaling in liver by relaxing its inhibition of gluconeogenesis mid-life adiposity is associated with β-amyloid burden, accelerated
and maintaining the activation of lipogenesis through the differential brain atrophy, and neurodegeneration, accelerating the clinical
expression of IRS-1 and IRS-2 in periportal and perivenous zones of course of AD.199 This study also showed that every unit increase in
liver.184 In obesity and ageing, the peripheral insulin resistance, mid-life BMI advances the onset of AD by 6.7 months. Oppositely,
ectopic fat accumulation in skeletal muscle, and β cell dysfunction the onset of AD can be delayed by a healthy mid-life BMI profile.
impair the functions of the corresponding organs and, together, drive Recently, a number of interactions between genetic variation and
the development of T2DM. obesity have been identified. ApoE4 (ε4 allele of apolipoprotein E) has
14 TAM ET AL.

been suggested to interact with obesity to increase the risk of AD.200 promote genome instability and cancer development. Besides
Diet-induced obesity in mice affects apoE4, leading to an acceleration destabilizing the human genome and inducing mutations, metabolic
of AD-related pathology by increasing β-amyloid accumulation, a hall- dysregulation that results from excess adiposity may fuel the growth
mark of AD.97 Another study focusing on non–diet-induced obesity of cancer cells.227,228
has revealed that the obesity-related gene (FTO) interacts with apoE4 Recently, multiple studies have shown that cancer cells with
and may increase the risk for AD by approximately 300%.201 A partial increased expression of fatty acid receptor, CD36, are able to initiate
explanation for this interaction is that the greater appetite and higher metastasis and promote self-renewal.229-231 It is particularly notewor-
fat intake in FTO occur simultaneously with the inefficient removal of thy that omental adipocytes are able to induce expression of CD36 in
lipid content in circulation caused by apoE4.202,203 The combined ovarian cancer.232 We speculate that central obesity would increase
effects appear to lead to the predisposition of early-onset AD in car- the risk of intra-abdominal tumours as the excess omental fat is likely
204,205
riers of these alleles with obesity. Another mechanism by which to increase the direct transfer of lipids from adipocytes to cancer
obesity may increases the risk of AD is through alterations in leptin cells.232 High-fat diet also increases metastatic potential of CD36+
and inflammatory signalling in the central nervous system, which cancer cells. CD36+ cancer cells acquire energy from β-oxidation of
increase food intake, accumulation of β-amyloid, and microvascular fatty acids enabling self-survival at sites far away from the primary
206-208
disease. 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-
5.6 | Cancer terol, allowing cancer cells to flexibly adapt to the tumour micro-
environment.
As one ages, numerous cell divisions result in an increase in the accu- In obesity, the dysfunctional adipose tissue is known to activate
mulation of harmful mutations, which can ultimately evolve into dis- multiple pathways that support cell proliferation, cell survival, inva-
eases such as cancer.209 According to the United States Cancer sion, metastasis, and angiogenesis in cancer.233 SASP has also been
210
Statistics, compared with those aged between 40 and 44, the inci- demonstrated to play a crucial role in promoting obesity-associated
dence of cancer in those over 70 years is about eight times higher. hepatocellular carcinoma in mice. Obesity alters gut microbiota and,
Statistics from Cancer Research UK show the same trend, with half of hence, increases production of deoxycholic acid (DCA), which causes
all cancers affecting patients over the age of 70.211 It is suggested that DNA damages through redox imbalance.234 The elevated DCA
intrinsic risk factors (eg, age) only contributes 10% to 30% to cancer induces cellular senescence and provokes SASP in hepatic stellate
development, while extrinsic risk factors (eg, obesity) contribute to cells, which in turn produce proinflammatory factors to promote the
the rest of cancer development.212 development of hepatocellular carcinoma. Therefore, not only does
Epidemiological studies indicated that 35% of cancers can be obesity alter the adipokine profiles in individuals with excess adipos-
213
attributed to dietary factors and obesity. These studies revealed ity, it may also cause cellular senescence in stellate cells, inducing
that excess adiposity increases the relative risk of cancers 1.1 to 7.1 senescence secretomes that promote tumourigenesis and cancer
times, including (in the order of increasing relative risk) thyroid, breast, development.
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 6 | CONC LU SIONS
with a 10% risk reduction of all cancers.222 Interestingly, the benefits
of weight reduction in females seem to be more promising. Bariatric In this review, we show that obesity and ageing are “two sides of the
surgery has been associated with 44% risk reduction of endometrial same coin” by demonstrating how the pathology of obesity parallels
cancer.223 Furthermore, weight loss of 5 kg or more after age 18 has those of ageing at multiple levels from the molecular to systemic. At
been shown to reduce risk of postmenopausal breast cancer.224 Col- the molecular level, both obesity and ageing promote cellular senes-
lectively, though cancer has traditionally been associated with ageing, cence, inflammation, and mitochondrial dysfunction through redox
there is strong evidence showing that obesity is associated with imbalance and insufficient autophagy. The accumulation of
higher risk of cancers and the absence of excess body fat reduces the malfunctioning mitochondria in obesity leads to chronic inflammation
risk of cancers. that reinforces the senescence-associated secretory phenotypes of
Obesity could fuel the initiation, progression, and metastasis of ageing. The inhibition of autophagy in obesity results in further aggre-
cancer through pathways that parallel ageing including ROS genera- gation of misfolded proteins, which are common features of ageing.
tion, inflammation, and altered molecular signalling in cancer cells. In Moreover, the attrition of telomeres, which is characteristic of ageing,
addition to mutations that accumulate steadily through normal ageing, is also observed in obesity. Another indicator of ageing, the epigenetic
obesity may induce additional mutations through genotoxic sub- clock, is also accelerated in obesity. These molecular and cellular
28,225,226
stances and, hence, accelerate the onset of cancer. Obesity- changes that are subsequent to both obesity and ageing have a pro-
associated metabolites, such as 8-oxo-20 -deoxyguanosine, found impact on human health, hastening the development of age-
4-hydroxynonenal and 16α-hydroxyestrone, have been suggested to related conditions and diseases.
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