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Mechanisms of Ageing and Development
journal homepage: www.elsevier.com/locate/mechagedev
Aging Fits the Disease Criteria of the International Classification of Diseases
Daria Khaltourina
a,e
, Yuri Matveyev
b
, Aleksey Alekseev
c
, Franco Cortese
d
, Anca Ioviţă
e
a
Department of Risk Factor Prevention, Federal Research Institute for Health Organization and Informatics of Ministry of Health of the Russian Federation, Dobrolyubova
St. 11, Moscow, 127254, Russia
b
Research Lab, Moscow Regional Research and Clinical Institute, Schepkina St. 61/2 k.1, Moscow, 129110, Russia
c
Faculty of Physics, Lomonosov Moscow State University, Leninskie Gory, GSP-1, Moscow, 119991, Russia
d
Biogerontology Research Foundation, Apt 2354 Chynoweth House, Trevissome Park, Truro, London, TR4 8UN, UK
e
International Longevity Alliance, 19 avenue Jean Jaurès, Sceaux, 92330, France
ABSTRACT
The disease criteria used by the World Health Organization (WHO) were applied to human biological aging in order to assess whether aging can be classified as a
disease. These criteria were developed for the 11th revision of the International Classification of Diseases (ICD) and included disease diagnostics, mechanisms, course
and outcomes, known interventions, and linkage to genetic and environmental factors.
Results: Biological aging can be diagnosed with frailty indices, functional, blood-based biomarkers. A number of major causal mechanisms of human aging involved
in various organs have been described, such as inflammation, replicative cellular senescence, immune senescence, proteostasis failures, mitochondrial dysfunctions,
fibrotic propensity, hormonal aging, body composition changes, etc. We identified a number of clinically proven interventions, as well as genetic and environmental
factors of aging. Therefore, aging fits the ICD-11 criteria and can be considered a disease. Our proposal was submitted to the ICD-11 Joint Task force, and this led to
the inclusion of the extension code for “Ageing-related”(XT9T) into the “Causality”section of the ICD-11. This might lead to greater focus on biological aging in
global health policy and might provide for more opportunities for the new therapy developers.
1. Introduction
Aging (hereafter biological aging) can be defined as a complex in-
terrelated network of progressive functionally-deleterious phenotypic
deviations (with respect to the young adult phenotype) underlying
biological aging, leading to a decline in individuals’adaptability, phy-
siological and mental function, as well as resilience.
There are discussions of whether aging should be classified as a
disease or not. A number researchers argued that aging should be
considered and treated as a disease (Bulterijs et al., 2015;de Grey and
Rae, 2007;Lakatta, 2015;Stambler, 2017;Zhavoronkov and Bhullar,
2015). The WHO developed a definition of disease for the purposes of
11th ICD revision:
“A disease is a set of dysfunction(s) in any of the body systems
defined by: 1. Symptomatology: manifestations: known pattern of signs,
symptoms and related findings 2. Aetiology: an underlying explanatory
mechanism 3. Course and outcome: a distinct pattern of development
over time 4. Treatment response: a known pattern of response to in-
terventions 5. Linkage to genetic factors: e.g., genotypes, patterns of
gene expression 6. Linkage to interacting environmental factors”
(World Health Organization, 2011).
We undertook an effort to determine whether aging fits the ICD
definition of disease as per the current state of medical research. An
earlier version of this review was submitted to the WHO, which resulted
in the addition of the WHO ICD extension code "Ageing-Related" (XT9T)
for aging-related diseases in the “Causality”section of the ICD-11
(Calimport and Bentley, 2019).
2. Materials and methods
To obtain information on signs and symptoms of aging we screened
the most clinically relevant studies of aging biomarkers, including vast
amounts of research literature on frailty indices. The analysis of the
aetiology and underlying explanatory mechanisms of aging were per-
formed in several stages.
We initially produced a comprehensive list of aging-related patho-
logical processes, with some but not all of them being listed in ICD-10
as separate diseases, and others added from research literature
(Supplementary Table S1). We then screened medical research litera-
ture for reviews of the mechanisms of these aging-related pathological
processes and diseases in humans at the level of organs, tissues, cells,
signaling molecules, pathways, gene expression and interventions.
Animal research was reviewed as subsidiary when it covered important
knowledge gaps about certain aging-related cellular processes, mole-
cular pathways or epigenetic changes associated with aging and dis-
eases. We also reviewed pathogenetic processes of aging identified in
biogerontological research literature (de Grey and Rae, 2007;López-
Otín et al., 2013). Additionally, we documented clinical studies and
https://doi.org/10.1016/j.mad.2020.111230
Received 5 February 2019; Received in revised form 4 March 2020; Accepted 9 March 2020
E-mail address: khatourina@mednet.ru (D. Khaltourina).
Mechanisms of Ageing and Development 189 (2020) 111230
Available online 03 April 2020
0047-6374/ © 2020 Published by Elsevier B.V.
T
animal research on the effects of potential geroprotective interventions
on all-cause and cardiovascular mortality and other relevant clinical
endpoints in humans, as well as on lifespan of model organisms. We
documented the findings on cellular and molecular mechanisms of
aging-related pathological processes and the beneficial effects of ger-
oprotective interventions.
3. Results
3.1. Symptomatology and the course of disease
Large-scale cohort studies in humans and detailed investigations
into the biology of human aging provide individually validated bio-
markers and mechanisms, potentially leading to recommendations for
targeted interventions (Jia et al., 2017;Moeller et al., 2017).
3.1.1. Blood-based biomarkers of aging
A number of large studies identified sets of blood-based biomarkers
of aging which retrospectively predict morbidity and mortality in large
cohort studies and clinical trials (Bürkle et al., 2015;Horvath, 2013;
Moeller et al., 2017;Putin et al., 2016). These kinds of studies provide
tools for predicting clinically significant aging-related outcomes, like
risks of morbidity, mortality, aging related diseases (Sebastiani et al.,
2017), cognitive or physical function decline or frailty.
Some proposed (Wagner et al., 2016) clinically significant blood-
based biomarkers of aging include inflammation agents, such as inter-
leukin-6 (IL-6) (Holly et al., 2013;Mitnitski et al., 2015;Sebastiani
et al., 2017;Soysal et al., 2016), TNF-a (Langmann et al., 2017;
Nascimento et al., 2018), C-reactive protein (CRP) (Sebastiani et al.,
2017;Soysal et al., 2016;Velissaris et al., 2017), and other in-
flammatory markers, glucose metabolism biomarkers such as glycated
hemoglobin (HbA1c) (Belsky et al., 2015) and plasma glucose
(Mamoshina et al., 2018;Wood et al., 2019;Zaslavsky et al., 2016),
adipokines (Mitnitski et al., 2015), homocysteine (Crimmins et al.,
2008;Mitnitski et al., 2015), thyroid hormones (Suzuki et al., 2012), N-
terminal prohormone of brain natriuretic peptide (NT-proBNP) (Draper
et al., 2018;Raymond, 2003), as well as troponin, albumin (Bouajila
et al., 2018) or albumin/creatinine ratio (Mitnitski et al., 2015;Putin
et al., 2016), lipid biomarkers such as low-density lipoprotein choles-
terol (LDL-C) (Carreira et al., 2012;Sebastiani et al., 2016), and tri-
glycerides (TGs) (Irvin et al., 2018;Rhee et al., 2019).
3.1.2. Function-based and anthropometric biomarkers
Clinically significant physical function and anthropometric bio-
markers of aging include walking speed, standing from a chair, walking
balance, grip strength (Kim et al., 2018a), body mass index (BMI)
(Ismail et al., 2002;Muñoz et al., 2010), waist circumference, muscle
mass (Kim et al., 2016c) and others (Wagner et al., 2016).
3.1.3. Aging-related frailty and Frailty Indices
Fried et al. described frailty phenotype criteria including uninten-
tional weight loss, self-reported exhaustion, weakness (grip strength),
slow walking speed, and low physical activity (Fried et al., 2001).
Frailty Index was suggested (Mitnitski et al., 2001) as a proxy measure
of aging, and thus can be used (although crudely) as a metric that al-
lows researchers and clinicians to compare the rates of aging between
individuals and populations (Rockwood et al., 2005;Rockwood and
Mitnitski, 2007).
Prevalence of pre-frailty and frailty significantly increases with age,
with pre-frailty prevalence reaching as high as 47% in old age, ac-
cording to some studies (Buckinx et al., 2015). Yet, frailty is related to
biological age stronger than to chronological age (Romero-Ortuno and
Kenny, 2012).
ICD-10 includes the R54 code for “Senility”, while ICD-10-CM codes
this condition as "Age-related physical debility". However, frailty has
become an established term after the introduction of the Rockwood
Frailty Scale in 2005 (Rockwood et al., 2005).
Frailty indices (FIs) are often used in epidemiological and clinical
studies to monitor health and to predict mortality and morbidity risks.
A number of similar FIs which are currently used (Jeong et al., 2013;
Rockwood et al., 2005) correlate better than calendar age with many
clinically significant endpoints, including mortality (Ravindrarajah
et al., 2013), postoperative outcomes (Lin et al., 2016), sexual health
(Lee et al., 2012), cancer survival (Ommundsen et al., 2014), etc.
Frailty can be currently measured starting from the age as young as
15 (Rockwood et al., 2011). A number of lifestyle, nutraceutical and
pharmaceutical interventions have been proposed, developed and used
to prevent or reduce frailty levels (Cesari et al., 2015).
3.1.4. Combination of blood-based biomarkers with Frailty indices
Mitnitski et al. (Mitnitski et al., 2015) analyzed 40 biomarkers of
cellular aging, inflammation, hematology and immunosenescence using
baseline data and 7-year mortality data from the Newcastle 85+ Study,
characterized the discriminatory ability of this biomarker-based frailty
index (FI-B) to predict mortality compared to individual biomarkers,
and then combined this FI-B with a clinical deficits frailty index (FI-C)
to see whether the combined FI-B and FI-C index possessed greater
ability to predict mortality than the FI-B alone. The biomarkers which
were significant predictors of mortality included blood-based in-
flammation biomarkers such as high sensitivity CRP, leptin, adipo-
nectin, homocysteine, albumin, hematological biomarkers (he-
moglobin, platelets, white blood cell count, neutrophils, lymphocytes),
biomarkers of immunosenescence, as well as transforming growth
factor β(TGF-β), and insulin-like growth factor-binding protein 1
(IGFBP1).
The researchers found that the FI-B has significantly greater dis-
criminatory accuracy to predict mortality than any one biomarker or
biomarker subgroup alone, and that the combined FI-B and FI-C index
possessed the greatest overall ability to predict mortality.
3.1.5. Genetic biomarkers of aging
A number of genetic biomarkers of aging have been proposed, in-
cluding telomere length (Zhang et al., 2014b), T-cell DNA rearrange-
ment (Zubakov et al., 2010) and DNA methylation, as well as some
other epigenetic modifications (Pal and Tyler, 2016).
Methylation patterns of certain CpG sites in DNA are highly corre-
lated with age. A number of epigenetic aging scores have been devel-
oped with high ability to predict mortality (Fransquet et al., 2019;Gao
et al., 2019) and calendar age including Horvath’s epigenetic clock
(Horvath, 2013), epigenetic clock by Hannum et al. (Hannum et al.,
2013), GrimAge (Lu et al., 2019), and others (Horvath et al., 2018;
Weidner et al., 2014). Some epigenetic clocks measure accelerated
aging including DNAmPhenoAge acceleration (Levine et al., 2018) and
AgeAccelGrim (Lu et al., 2019). Data suggest that these epigenetic
aging clocks may be altered by lifestyle (Quach et al., 2017;Zhao et al.,
2019b) or, possibly, by some therapeutic interventions (Fahy et al.,
2019;Sae-Lee et al., 2018). Future clinical research will reveal how
relevant these indicators are in practice.
3.1.6. Indices of biological age
A large number of indices of biological age have been proposed.
Some biological age formulas measure biological aging per se with a
number of biomarkers (Jia et al., 2017), while a number of research
groups use Klemera and Doubal’s method in such indices, which adds
age acceleration (deceleration) to calendar age (Klemera and Doubal,
2006). Other groups used indicators of pathologies (Hochschild, 1989)
or artificial intelligence methods to create indices of biological aging
(Putin et al., 2016;Pyrkov et al., 2018;Rahman and Adjeroh, 2019).
In sum, there is a growing number of diagnostic tools which can be
used to assess the rate of biological aging, to develop new medicines
and to monitor effectiveness of interventions. Research on FIs reached
considerable degree of consensus, while the research on blood-born,
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
2
epigenetic and other biomarkers is gaining momentum. Therefore,
aging diagnostics is already available and is developing further.
3.2. Aetiology: an underlying explanatory mechanism
We performed a search in the medical research literature and
identified a number of interrelated pathological processes which are
known to take part in the pathological aging-related processes and
changes of various systems and structures of the human body listed in
Table S1.
3.2.1. Chronic low-grade inflammation
Aging-related chronic low-grade inflammation ("inflamm-aging") is
described by the increase in inflammatory markers and agents in aging,
in the absence of overt infection (“aseptic”inflammation).
There is overwhelming epidemiological evidence that the state of
mild inflammation, revealed via elevated levels of inflammatory bio-
markers such as CRP, IL-6 (Mitnitski et al., 2015;Soysal et al., 2016),
and potentially a few other inflammation biomarkers, is predictive of
many aging phenotypes, such as changes in body composition, energy
production and utilization, metabolic homeostasis, immune senescence,
neuronal health and frailty (Franceschi and Campisi, 2014).
Circulating proinflammatory molecules are strong predictors of age-
related morbidity and mortality (Barron et al., 2015;Li et al., 2017b).
There is mounting clinical evidence that local production of in-
flammatory cytokines can drive phenotypes and pathologies associated
with aging, including atherosclerosis (Lorenzatti and Retzlaff, 2016),
diabetes (Park et al., 2014), pulmonary diseases (Franceschi and
Campisi, 2014;Murray and Chotirmall, 2015), and Alzheimer's disease
(AD) (Franceschi and Campisi, 2014).
Neuroinflammation is the major route of nervous system aging and
degenerative disease development (Yin et al., 2016).
Aging-related increase in the levels of pro-inflammatory cytokines is
caused by replicative cellular senescence (Coppé et al., 2010), increased
body fat share, mitochondrial damage, damaged macromolecules (Shi
et al., 2015) and cells (self-debris) that accumulate with age due to
increased production and/or inadequate elimination (Franceschi and
Campisi, 2014) and microbiota changes (Nagpal et al., 2018).
Exercise (Monteiro-Junior et al., 2018) and the decreased BMI leads
to decrease in serum inflammatory markers (Fedewa et al., 2017). Both
physical exercise (Naci and Ioannidis, 2013) and intentional weight loss
in people with preexisting obesity (Kritchevsky et al., 2015) are asso-
ciated with reduced all-cause mortality.
Healthy dietary patterns are also associated with lower in-
flammatory markers (Soltani et al., 2017). The consumption of olive oil
(Schwingshackl et al., 2015) as well as nuts (Neale et al., 2017) de-
creases inflammation markers and reduces the risks of cancer incidence
(Pelucchi et al., 2011), cardiovascular and all-cause mortality (Chen
et al., 2017b;Schwingshackl and Hoffmann, 2014). Coffee consumption
also reduces serum concentration of CRP (Zhang and Zhang, 2018), and
may reduce cancer incidence (Poole et al., 2017).
Vitamin D supplementation decreases CRP level (Mirhosseini et al.,
2018), and it may also reduce all-cause mortality in adults (Chowdhury
et al., 2014) and cancer risks (Grant, 2018), perhaps due to high rates of
vitamin D deficiency in the modern societies. There is evidence that the
use of aspirin, an anti-inflammatory drug, is associated with modestly
reduced all-cause, cardiovascular mortality (in non-hypertensive sub-
jects) and cancer prevalence, as well as mortality in older adults
(Sutcliffe et al., 2013;Whitlock et al., 2015).
Therefore, all the above-mentioned interventions can be viewed as
both anti-inflammatory and geroprotective (capable of addressing pa-
thological aging processes and extending lifespan in humans).
Glucosamine and chondroitin use reduces CRP in healthy subjects
(Navarro et al., 2015), and may be associated with reduction in all-
cause mortality, mortality from cancer and respiratory diseases, ac-
cording to the observational studies (Bell et al., 2012).
Other potential anti-inflammatory interventions with some systemic
health benefits include acipimox (Liang et al., 2013), quercetin
(Mohammadi-Sartang et al., 2017;Sahebkar, 2017;Serban et al., 2016),
coenzyme Q10 (CoQ10) (Zhai et al., 2017), ginger (Mazidi et al., 2016),
resveratrol (Guo et al., 2017), magnesium (Simental-Mendia et al.,
2017), and arnesin/carnosine (Hisatsune et al., 2016;Menon et al.,
2018), melatonin (Akbari et al., 2018), curcumin (Tabrizi et al., 2018b),
liraglutide (Kahal et al., 2014), telmisartan (Takagi et al., 2013), sil-
denafil(Santi et al., 2015), pentoxifylline (Pollice et al., 2001), as well
as probiotic (Mazidi et al., 2017), prebiotic and symbiotic supplements
(McLoughlin et al., 2017).
3.2.2. Replicative cellular senescence
Cellular senescence refers to the durable arrest of cell proliferation
that occurs when cells experience certain types of alterations, including
telomere shortening and activation of damage sensing pathways, such
as p38 mitogen-activated protein kinases (p38
MAPK
) and nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-κB) (Campisi, 2013;
He and Sharpless, 2017). The majority of senescent cells can be de-
tected via beta-galactosidase assay, estimation of Lamin B1 loss and
markers of senescence-associated secretory phenotype (SASP).
Both telomere shortening in various tissues (Ishikawa et al., 2016)
and the accumulation of post-mitotic senescent cells increase with age
(Belsky et al., 2015;Liu et al., 2009;Sørensen et al., 2016).
Telomere length (TL) correlates negatively with the risks of cardi-
ovascular (Akasheva et al., 2015;Dudinskaya et al., 2015;Haycock
et al., 2014;Strazhesko et al., 2015), neurodegenerative (Forero et al.,
2016), lung (Calhoun et al., 2016) diseases, and mortality in people
aged 60 and over (Cawthon et al., 2003;Sørensen et al., 2016), as well
as in cancer survivors (Xu et al., 2016).
Telomere shortening is a major pathway of cellular senescence.
When telomeres reach critical shortness, the cell enters either senes-
cence, normally through the induction of cyclin-dependent kinase in-
hibitor 2A (p16
INK4a
), or apoptosis. The intracellular enzyme telo-
merase can promote telomere lengthening, preventing the age-related
shortening that comes with cell division.
Additionally, cellular senescence can be induced by stressors like
mitochondrial or DNA damage, oxidative stress (Reichert and Stier,
2017), as well as the use of cytotoxic/genotoxic therapies.
The causal mechanisms for the associations between age-related
increase in cellular senescence and the disease pathogenesis include
pro-inflammatory and pro-fibrotic SASP of senescent cells, the loss of
proliferation-competent cells, and the reduction of the total number of
functional tissue cells.
SASP has been shown to drive local and systemic inflammation
accompanied by macrophage and lymphocyte infiltration, apoptosis
and fibrosis. Recent evidence in fibroblasts and epithelial cells has
shown that cellular senescence is accompanied by a striking increase in
the secretion of 40–80 factors that participate in intracellular signaling.
SASP proteins are generally induced at the level of mRNA and include a
wide range of growth factors, proteases, chemokines and cytokines.
Proteins that are known to stimulate inflammation, including IL-6, IL-8,
IL-1, granulocyte macrophage colony-stimulating factor (GM-CSF),
growth regulated oncogene (GRO)-α, monocyte chemotactic proteins
(MCPs) MCP-2, MCP-3, matrix metalloproteinases (MMPs) MMP-1,
MMP-3, and many of the insulin-like growth factor-binding proteins
(IGFBPs), are among the most robustly induced and secreted of these
factors (Freund et al., 2010).
While cellular senescence may play a protective role in some con-
ditions like wound healing, cancer or fibrosis, the burden of senescent
cells seems to be net-detrimental for aging organisms. Replicative arrest
is oncoprotective, however, on the other side, SASP induction by the
senescent cells might promote cancer. Also, senescent cells can com-
promise tissue cancer resistance capacity. These findings open oppor-
tunities for new therapeutic approaches to the treatment of age-related
diseases (Hodes et al., 2016).
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
3
There are numerous examples of involvement of senescent cells in
the pathogenesis of the diseases of aging, including CVDs (Alique et al.,
2018;Krouwer et al., 2012;Wang and Bennett, 2012), AD (Bhat et al.,
2012;Ojo et al., 2015), glaucoma (Liton et al., 2005), cataract (Zhou
et al., 2015), and osteoarthritis (McCulloch et al., 2017).
The interventions which prevent or reduce the harmful effects of
cellular senescence are still being explored.
Physical activity (Mundstock et al., 2015) and healthy dietary pat-
terns, such as Mediterranean diet, as well as fruit and vegetable con-
sumption might be related to longer telomere length (TL), while con-
sumption of certain food categories including processed meat, cereals
and sugar-sweetened beverages, as well as excessive red meat con-
sumption may be associated with shorter TL (Rafie et al., 2017).
Also, metformin use might be associated with larger telomere length
in prediabetic subjects (de Kreutzenberg et al., 2015).
Statins modulate telomerase activity and reduce telomere erosion
(Boccardi et al., 2013;Paradisi et al., 2012), while atorvastatin acti-
vates telomerase in patients free of atherosclerosis (Strazhesko et al.,
2016).
Some other potential pharmacological interventions against cellular
senescence have been identified, but their effects and toxicity still need
to be studied. For example, quercetin is known to promote apoptosis in
senescent cells (Khan et al., 2016).
Cycloastragenol (TA-65, Astragalus propinquus extract) is pur-
ported to have telomerase activation activity. Astragalus may be ben-
eficial for patients with non-small-cell lung (He et al., 2013) and he-
patocellular cancers (Tian et al., 2016;Wu et al., 2009), and early
macular degeneration (Dow and Harley, 2016).
Lubricant eye drops with N-acetylcarnosine, a carnosine prodrug, at
physiological concentration might remarkably reduce the rate of telo-
mere shortening in the lens and improve visual functions in older
people (Babizhayev and Yegorov, 2016). At the same time, carnosine
supplementation may reduce oxidative stress (Regazzoni et al., 2016),
while anserin and carnosine supplements might improve cognitive
abilities and physical functioning in this group (Hisatsune et al., 2016;
Szcześniak et al., 2014).
Olive phenols might prevent cellular senescence (Menicacci et al.,
2017), but further research is needed.
3.2.3. Proteostasis failures
Protein homeostasis (proteostasis) is a network of biological path-
ways responsible for protein folding, trafficking, metabolism and de-
gradation within and outside cells, which is essential for health main-
tenance. Pathological processes of aging impose significant chronic
stress on proteostatic systems, which induces various subsequent cas-
cades of pathogenesis.
Aggregations of misfolded proteins in proteinaceous inclusions are
common to many age-related diseases, including cardiovascular,
kidney, liver, eye diseases, osteoporosis (Yamagishi et al., 2015), dia-
betes (Nenna et al., 2015), as well as neurodegenerative diseases, such
as AD and Parkinson's disease (PD) (Chiti and Dobson, 2017;Iannuzzi
et al., 2014).
Misfolded protein aggregation is found not only in patients with
certain diseases, for example, significant amyloid deposits are found in
20 to 30% of the brains of healthy older adults (Rodrigue et al., 2009).
Damaged macromolecules accumulate with age due to increased
production and/or inadequate elimination of certain proteins which
promotes pathological processes, both specific, including cognitive
decline and type 2 diabetes (T2D), and non-specific such as in-
flammation.
There are different mechanisms of misfolded protein toxicity.
Smaller oligomers are the major pathogenic source of the neuropathic
diseases of the central nervous system, as they interact with various
cellular structures including phospholipid bilayers of the cell membrane
and a number of cell receptors. At the same time, pathogenic species in
non-neuropathic systemic or localized amyloidoses include both
extracellular amyloid deposits affecting organ integrity and protein
oligomers that are produced during the process of their formation or are
released by mature deposits, causing direct cellular damage (Chiti and
Dobson, 2017).
Some misfolded proteins, including amyloid-beta (Aβ)(Lucia
Pagani, 2011), amylin (Lim et al., 2010), α-synuclein (Chiti and
Dobson, 2017), advanced glycation end products (AGEs) (Neviere et al.,
2016), advanced oxidation protein products (AOPPs) (Ye et al., 2017)
detrimentally affect mitochondrial function, induce oxidative stress and
apoptosis.
Healthy low levels of Aβpeptides might be needed for cGMP-in-
duced long-term potentiation and memory (Palmeri et al., 2017).
However, excess of Aβoligomers is a major contributor to AD, as they
interact with the phospholipid bilayers of the cell membrane, N-Methyl-
D-aspartic acid (NMDA) and AMPA receptors, the metabotropic gluta-
mate receptor 5, the insulin receptor, the nicotinic acetylcholine re-
ceptor α7-nAcChR, cellular prion protein (PrP
C
), and other cellular
components and membrane receptors leading to cognitive decline and
AD development (Benilova et al., 2012;Chiti and Dobson, 2017).
Misfolded tau protein is another major contributor of AD (Chiti and
Dobson, 2017).
Similarly, glycation of α-synuclein is a factor involved in the protein
aggregation in the formation of Lewy bodies and in PD development.
Age-related amylin accumulation induces inflammatory response in
pancreatic islets and apoptosis in insulin-producing beta cells, which is
strongly implicated in the progression of T2D (Singh et al., 2015). They
may also play a role in the pathogenesis of cardiac (Despa et al., 2012)
and cognitive dysfunctions (Ly and Despa, 2015;Qiu and Zhu, 2014).
AGEs are a diverse group of macromolecules formed through sugars’
covalent bonding to proteins, lipids, or nucleic acids as result of non-
enzymatic reaction, and they accumulate in organisms during aging.
There is a growing body of evidence that AGEs induce oxidative
stress generation through their receptor (RAGE) and as a result stimu-
late inflammatory, thrombotic, fibrotic and proliferative responses in a
variety of cells and tissues. AGEs and RAGE are involved in the devel-
opment of diabetes and aging-associated disorders such as cardiovas-
cular complications (Neviere et al., 2016), cancer, AD, osteoporosis
(Yamagishi et al., 2015), chronic kidney disease (CKD) (Nakamura
et al., 2010) nonalcoholic steatohepatitis (NASH) (Takeuchi et al.,
2017).
Some misfolded proteins “damage”-associated biomolecular sig-
natures initiate innate immune responses by being recognized as
“danger”signals by a network of sensors (including but not limited to
the Nlrp3 inflammasome) (Shi et al., 2015).
The burden of misfolded proteins increases in aging via different
mechanisms.
Proteins and other signaling molecules undergo various forms of
enzymatic and non-enzymatic post-translational modifications. Many of
these proteins are vital for the normal organism functioning, but
changes in the frequency of some of these modifications can lead to
dysfunction. Examples of protein post-translational modifications that
have been suggested to have causal links to aging, include glycation,
various forms of oxidative damage, nitration, enzymatic crosslinks,
deamidation, racemization, isomerization, and carbamylation.
Additionally, changes in glycosylation appear to act as clinical bio-
markers of aging in humans (Ding et al., 2011;Vanhooren et al., 2010).
Some of the health problems imposed by protein metabolism dis-
balances are caused by developmental processes and can be referred to
as programmed events. The most prominent example is elastic tissue
degradation, which leads to blood vessel stiffening, as well as aging of
lungs, skin, ligaments, etc.
The major part of elastic fiber formation takes place during prenatal
and early neonatal periods and is suppressed in adults by post-tran-
scriptional factors (Mora Huertas et al., 2016).
Additionally, elastin-derived peptides (EDPs) derived from elastic
tissue degradation, are involved in vascular, lung and renal diseases
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
4
(Duca et al., 2016;Smith et al., 2012). Elastolysis is mainly triggered by
elastases from inflammatory cells that secrete neutrophil elastase,
MMPs (especially MMP-2), and cathepsins. Higher serum levels of
MMP-2, cathepsins and EDPs were independently associated with
baseline aortic pulse wave velocity, and MMP-2 and EDP levels in-
dependently predicted all-cause mortality in a cohort study of people
with predialysis CKD (Smith et al., 2012). The downstream signaling of
EDPs involves spliced-galactosidase (s-Gal), NF-κB, Sialidase 1 (Neu-1),
ERC, M3 ganglioside, lactosylceramide, etc. (Duca et al., 2016).
Inadequate protein clearance is a mechanism implicated in many
pathological processes of aging. For example, decreased or inadequate
clearance of Aβleads to the accumulation of Aβoligomers and larger
aggregate formation (Kundra et al., 2017). Aging-related increase in
oxidative stress and decrease in mitochondrial function reduce the ef-
fectiveness of the proteostasis networks (Chiti and Dobson, 2017).
Many proteostatic processes and systems are impaired or over-
loaded during aging. Thus, the function of the chaperome, the ensemble
of chaperones and co-chaperones that interact in a complex network of
molecular folding machines to regulate proteome function, is drama-
tically repressed in human aging brains and in the brains of patients
with neurodegenerative diseases (Brehme et al., 2014).
Autophagy and proteasome activities have both been found to de-
crease with aging (Chiti and Dobson, 2017;Morimoto and Cuervo,
2014), but to a lesser extent in healthy centenarians (Emanuele et al.,
2014). Defective autophagy is assumed to play a role in some aging-
related conditions, like osteoarthritis (Li et al., 2016;Nakamura et al.,
2010), AD, PD (Kaushik and Cuervo, 2015), and cancer (Xie and Zhou,
2018).
Interventions to reduce the burden of misfolded proteins vary de-
pending on the protein species. Some of them are being explored yet
(Bartolome et al., 2018;Zhou et al., 2016).
Proper dietary (Hanson et al., 2013) and sleep regimes (Ooms et al.,
2014) might be helpful to reduce Aβlevels in the nervous system in at
least some demographic groups.
There is some evidence that 17β-estradiol administration reduces
plasma Aβ40 in HRT-naïve postmenopausal women (Baker et al.,
2003), although safety and effectiveness of various regimes of hormone
replacement therapy (HRT) against dementias for women is being
questioned (Marjoribanks et al., 2017).
Some innovative therapies like plasma exchange with 5% albumin
are promising against accumulation of Aβpeptides (Boada et al., 2017;
Cuberas-Borrós et al., 2018).
Anatural product dihydroergocristine can reduce the burden of Aβ
(Lei et al., 2015). Dihydroergocristine use may have been associated
with better survival in dementia patients in one cohort study (Wu et al.,
2015a).
Simvastatin use leads to decreased levels of misfolded p-tau181
protein in cerebrospinal fluids (Li et al., 2017a;Riekse et al., 2006).
Statin use may be associated with lower risks of cognitive decline
(Smith et al., 2017) and dementia (Chou et al., 2014;Geifman et al.,
2017).
Many interventions which reduce the burden of AGEs are known to
have beneficial health effects in older adults, including dietary mod-
ifications (Uribarri et al., 2003), anti-diabetic drugs (sodium/glucose
cotransporter 2 (SGLT2) inhibitors (Bekki et al., 2018)), some of an-
giotensin II receptor blockers (ARBs) (Honda et al., 2012;Rabbani
et al., 2012), some statins (Cuccurullo et al., 2006;Fukushima et al.,
2013;Kimura et al., 2010), or anti-oxidants such as carnosine
(Babizhayev et al., 2012), quercetin (Byun et al., 2017;Nenna et al.,
2015), and curcumin with Boswellia serrata (Chilelli et al., 2016).
3.2.4. Immune senescence
Aging is a risk factor for the immune system’s dysfunction (immune
senescence), which leads to significantly increased vulnerability to in-
fections, and poorer response to newly encountered antigens, as well as
weaker responses to vaccines and immunotherapies for cancer and
other diseases common in the older demographics (Pera et al., 2015).
A major causal mechanism of immune senescence is the decline in
the number of naïve T-cells (Vescovini et al., 2014) due to thymic in-
volution, T-cell cellular senescence and impaired homeostatic pro-
liferation (Bellon and Nicot, 2017). The loss of naïve T-cell population
correlates with frailty (Johnstone et al., 2017), mortality (Mitnitski
et al., 2015) and well as with the risks of certain non-communicable
diseases (Moro-García et al., 2015).
Aging-related metabolic changes, including hormonal changes (Pera
et al., 2015), low-grade inflammation, increased exposure of T-cells to
pro-inflammatory molecules, DNA damage and expansion of dysfunc-
tional T-cells clones are primary causal factors implicated in the pa-
thogenesis and progression of immune senescence.
At the same time, persistent viral load through lifespan and that of
cytomegalovirus (CMV), in particular is the major promoter of immune
senescence (Bellon and Nicot, 2017). CMV is highly prevalent world-
wide and persists in its host for life. In synergy with aging, it promotes
differentiation of CD8+ T-cells, and the acquisition of a low CD4:CD8
T-cell ratio, which is a marker of aging-related or a virus-mediated
depletion of CD8+ naïve T-cell pools, and which correlates in-
dependently with frailty, morbidity and mortality in older people
(Johnstone et al., 2017;Mitnitski et al., 2015;Weltevrede et al., 2016;
Wikby et al., 1998). This suggests that the loss of immune-competent T-
cells in combination with CMV persistence are among causal mechan-
isms of aging and age-related morbidity and mortality.
Some potential geroprotective interventions are known to improve
T-cell immunity. Regular exercise increases naïve T-cell count (Duggal
et al., 2018), improves immune function and results in lower incidence
of disease (Arem et al., 2015;World Health Organization, 2010). Fre-
quent acute (but not extreme) physical exercise may increase relative
CD8+ T-cell telomere length, and allow naïve T-cells to occupy "va-
cant" immune space and increase the naïve T-cell repertoire (Simpson
et al., 2010). Vaccine response in adults can be improved with pro-
biotics (Lei et al., 2017) or mammalian target of rapamycin (mTOR)
inhibitors (Mannick et al., 2014). Antiviral therapies which are effective
against CMV and some other viruses and can reverse the development
of immune senescence in mice (Beswick et al., 2013), and their pro-
phylactic use might reduce mortality among renal transplant (Reddy
et al., 2003) and allogeneic stem cell transplant (Marty et al., 2017)
patients. Long-term safety and effectiveness of these interventions in
terms of preventing immunosenescence needs to be explored.
3.2.5. Increased fibrotic propensity
Aging is associated with significantly increased risks of chronic fi-
broproliferative conditions, including hepatic, renal, heart, vascular,
and pancreatic fibrosis (Rosenbloom et al., 2017), idiopathic lung fi-
brosis (IPF), chronic obstructive lung disease (COPD), infertility (Briley
et al., 2016), erectile dysfunction (El-Sakka, 2011), (Karsdal et al.,
2014), as well as eye diseases with fibrotic components (glaucoma,
secondary cataract (Rosenbloom et al., 2017), retinopathies (Roy et al.,
2016), and dry eye disease).
Fibrosis develops as a reaction to damage, such as mechanical da-
mage, toxins, inflammation, oxidative stress, re-
nin–angiotensin–aldosterone system (RAAS) overactivation, hypoxia,
which all may lead to pathological accumulation of extracellular matrix
(ECM) protein. Formation of excess fibrous connective tissue in an
organ or tissue occurs as part of a reparative or reactive process (e.g.
wound healing). When a critical organ such as the heart, liver, kidney
or pancreas is affected by fibrosis it can lead to the loss of its integrity
and function, which can result in further cascades of systemic damage.
Also, reduced blue light transmission due to aging-related fibrotic eye
diseases may impair the photoentrainment of circadian rhythm leading
to sleep disorders (Ayaki et al., 2016), and, possibly, higher levels of
systemic inflammation (Kessel et al., 2011).
The TGF-βsuperfamily is the most important ECM regulator, which
plays important roles in embryogenesis and development, with TGF-β1
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
5
being the major pro-fibrotic protein (Hu et al., 2018). TGF-β1 signaling
increases with age (Parker et al., 2017;Wang et al., 2006), and it can be
exacerbated by diabetes (Meng et al., 2016;Mou et al., 2016;Qiao
et al., 2017). Insulin resistance (IR) and obesity-derived inflammation
may also lead to “meta-fibrosis”(excessive ECM formation) (Lark and
Wasserman, 2017).
Dysregulated signaling between certain molecules and pathways,
including TGF-β, in particular TGF-β1, SMAD, SNAI1, CTGF (con-
nective tissue growth factor) (Lipson et al., 2012), vascular endothelial
growth factor (VEGF) (Chaudhary et al., 2007), epidermal growth
factor receptor (EGFR), galectin-3 and lysyl oxidase homolog 2 (LOXL2)
as well as MTORC1 and MTORC2 via PI3K/AKT and Wnt pathways
(Meng et al., 2016), which can be stimulated by reactive oxygen species
(ROS) induced by reduced form of nicotinamide adenine dinucleotide
phosphate (NADPH) oxidases (especially Nox4), inflammatory cyto-
kines, such as IL-6, IL-1a, IL-13, IL-4, tumor necrosis factor (TNF-α)
(Lark and Wasserman, 2017), hypoxia (hypoxia-inducible factor 1-α,
HIF-1-α) and leading ultimately to endothelial-mesenchymal transition
and fibrosis formation (Li et al., 2017c). Activated fibroblasts, pericytes
and other cells increase production of collagen, fibronectin, α-smooth
muscle actin (α-SMA) and other ECM proteins. This leads to the pro-
duction and accumulation of sub-pools of cross-linked proteins that can
be termed the ‘end products’of fibrosis. Hypoxia, one of the systemic
factors of aging, also acts to increase SNAI1 level mediated by HIF-1-α.
Mechanisms of tissue remodeling and inflammation resolution leading
to clearance of fibrotic matrix by extracellular proteolysis and/or en-
docytosis are inadequate in fibrosis (Piera-Velazquez et al., 2016).
Within the course of fibrosis formation, proteases (such as MMP-9,
MMP-12, MMP-13), secreted as a part of the damage response, degrade
the existing ECM components and release various protein fragments
(neo-epitopes) into circulation (Giannandrea and Parks, 2014).
Fibrosis research is still in development. A number of interventions
with known anti-aging effects in certain groups of patients are shown to
inhibit liver fibrosis progression in humans, including healthy diet
(Perumpail et al., 2017), coffee consumption (Liu et al., 2015), statins
(Kim et al., 2017), aspirin (Poujol-Robert et al., 2014;Shen et al.,
2014), RAAS inhibitors (Kim et al., 2016b), and, possibly, liraglutide
(Kahal et al., 2014). In fact, RAAS targeting drugs, such as ACE in-
hibitors and ARBs prevent and sometimes even regress myocardial,
renal, hepatic, and muscle fibrosis and alleviate COPD symptoms (Garg
et al., 2015;Shrikrishna et al., 2012).
N-Acetylcysteine (NAC), an antioxidant drug, improves symptoms
of COPD (Firuzi et al., 2011), and it could be effective in other fibrotic
conditions, including renal diseases (Ahmadi et al., 2017), liver failure
(Chughlay et al., 2016), myocardial infarctions (Talasaz et al., 2014).
Dasatinib plus quercetin combination may alleviate idiopathic pul-
monary fibrosis (Justice et al., 2019).
CoQ10 and selenium supplementation may lead to less fibrosis in
the older people, which may explain lower cardiovascular and all-cause
mortality in one study (Alehagen et al., 2018;Lehagen et al., 2018).
Additionally, cGMP-specific phosphodiesterase type 5 (PDE5) in-
hibitors, the NO-inducing drugs that address erectile dysfunction, seem
not only to prevent and reverse penile fibrosis (El-Sakka, 2011), but
also to reduce mortality in men with CVDs including myocardial in-
farctions (Andersson et al., 2017) and diabetes (Hackett et al., 2017).
Pentoxifylline, a non-selective phosphodiesterase (PDE) inhibitors may
be effective against miscellaneous fibrotic conditions (Wen et al., 2017)
and preserve kidney function in CKD (Chen et al., 2017c).
A number of interventions reduce arterial stiffness, including phy-
sical exercise (Zhang et al., 2018b) and RAAS blockers and metformin
(Wu et al., 2015a).
3.2.6. Aging-related mitochondrial dysfunctions
Mitochondria are organelles in charge of energy (adenosine tri-
phosphate, ATP) production, cellular respiration, storage of calcium
ions (Ca
2+
), regulation of cellular apoptositis, etc.
Mitochondrial respiratory chain dysfunction is a hallmark of aging
and manifests in decreased ATP and nicotinamide adenine dinucleotide
+ (NAD+) production, as well as excessive oxidative stress. It is in-
volved in major pathogenetic processes of aging, including inflamma-
tion (Picca et al., 2018), cellular senescence (Reichert and Stier, 2017;
Schuliga et al., 2018), IR (Jin and Diano, 2018;Tardito, 1990), im-
paired proteostasis (Chiti and Dobson, 2017;Kaushik and Cuervo,
2015), decreased stem cell functionality (Zhang et al., 2018a), muscle
loss (Coen et al., 2013;Doria et al., 2012), and neurodegeneration
(Brooks et al., 2007;Mosconi et al., 2006).
Aging-related mitochondrial dysfunctions affect multiple body sys-
tems, while energy-intensive organs like muscles (Coen et al., 2013;
Doria et al., 2012) or the nervous system are particularly vulnerable.
For example, AD is also accompanied by decreased mitochondrial
bioenergetics (Brooks et al., 2007), which can occur as early as a decade
before the diagnosis (Mosconi et al., 2006).
The hallmarks of aging-related mitochondrial dysfunctions include
mitochondria loss in aging, decreased ATP and NAD+ production,
impaired mitochondrial membrane function, swollen mitochondria,
damaged cristae, decreased mitochondrial DNA copy number, and ex-
cessive burden of ROS (Giuseppe and Ross, 2016). Decline in mi-
tochondrial biogenesis, cellular NAD+, ATP levels, decreased NAD
+/NADH ratio (Ying, 2008;Zhu et al., 2015), increased NADPH/NADP
+ ratio (Clement et al., 2018), decreased activity of mitochondrial
enzymes, as well as increased oxidative stress, all are observed in older
individuals. Data on ATP changes with aging suggests that there is an
average decline of 8% per decade in ATP producing capacity in skeletal
muscles (Payne and Chinnery, 2015).
Mitochondrial DNA mutations and reduced mitophagy lead to an
increased share of dysfunctional mitochondrial subclones (Bua et al.,
2006;Payne and Chinnery, 2015;Williams et al., 2013;Yu-Wai-Man
et al., 2010;Zheng et al., 2012), which is involved in a number of
pathological processes, including macular degeneration
(Karunadharma et al., 2010) and muscle aging (Brierley et al., 1998).
Mitochondrial biogenesis is progressively impaired in aging. This
includes decline in the number of mitochondria per cell, pathologic
morphology and physiology, as well as functional changes (Bianchi
et al., 2013;Peterson et al., 2012;Vega et al., 2015). Decrease in mi-
tochondrial biogenesis in aging is affected by various types of damage
and mitochondrial defects. Peroxisome proliferator-activated receptor
gamma coactivator 1α(PGC-1α) is the master regulator of mitochon-
drial biogenesis, and age-related decline in its activators, including
AMP-activated protein kinase (AMPK), NAD-dependent deacetylase
sirtuin-1 (SIRT1), NO and cGMP, or PGC-1αdownstream effectors, such
as peroxisome proliferator-activated receptors (PPARs), estrogen-re-
lated receptors (ERRs), Nuclear Respiratory Factor 1 (NRF1) and Nu-
clear Respiratory Factor 2 (NRF2), can improve mitochondrial output
(Suliman and Piantadosi, 2016). Induction of cellular tumor antigen
p53 by cellular stress, including telomere attrition, compromises mi-
tochondrial biogenesis affecting negatively PGC-1α(Sui et al., 2016).
Mitochondrial dysfunctions and subsequent cellular apoptosis can
be caused by cell damage, calcium ions (Ca
2+
)(Giorgi et al., 2015),
ROS signalling, IR and obesity (Ptitsyn et al., 2006), excess free fatty
acids (FFAs) (Di Paola and Lorusso, 2006), or misfolded proteins (Baud
et al., 2013;Payne and Chinnery, 2015).
NAD+ deficiency is mediated at least partially by an increase in
CD38 protein expression, which can be induced by inflammation, toxins
(Chini et al., 2018), ROS, and endogenous vasoconstrictors (Lee et al.,
2015). Overactivation of poly (ADP-ribose) polymerase (PARP) due to
DNA damage and repair can also reduce NAD+ levels. Age-related
reductions in nicotinamide phosphoribosyltransferase (NAMPT) levels
is another possible source of NAD+ deficiency (Chini et al., 2018).
ATP shortage is associated with muscle (Marzetti et al., 2013) and
cardiac (Yaniv et al., 2013) aging, and possibly with proteostasis fail-
ures (Brehme et al., 2014).
Aging-related defects of mitochondrial respiration include
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
6
pathological changes in the turnover of ROS, that are naturally occur-
ring byproducts of mitochondrial metabolism. They also play a role in
immune defense and act as signaling molecules. At the same time,
oxidative stress plays significant roles in aging, many of which have yet
to be investigated. However, some pro-longevity interventions, such as
physical exercise (Radak et al., 2013) or caloric restriction (Nisoli et al.,
2005) lead to increased mitochondrial biogenesis and, as a result,
higher ROS levels, which is, however, combined with improved anti-
oxidant defense. Therefore, dysregulated ROS metabolism, including
the impairment of antioxidant defense and oxidation product clearance
systems lead to the increased ROS burden (Guest et al., 2014;Massudi
et al., 2012) and health deterioration seen in aging (Payne and
Chinnery, 2015).
ROS are implicated in the development of cardiovascular (Gracia
et al., 2017;Puca et al., 2013) and neurodegenerative diseases (Kim
et al., 2015a), aging of cartilage tissues (Ye et al., 2017), liver (Zhang
et al., 2014a) and bladder (Camões et al., 2015), fibrosis, cancer (Morry
et al., 2017) as well as fertility decline in men (Gunes et al., 2016) and
women (Briley et al., 2016).
The burden of ROS, inflammation, cellular senescence (Calhoun
et al., 2016), immune senescence, oxidative stress (Lowery et al., 2013),
and misfolded protein damage (Baud et al., 2013) all promote the in-
duction of mitochondrial transition pore permeability. Mitochondrial
membrane impairment causes inadequate Ca
2+
signalling, which leads
to cell apoptosis and contributes to the development of cardiac (Dai
et al., 2012), neurodegenerative (Liao et al., 2017), muscular, cardiac
(Dai et al., 2012), and eye (Gauthier and Liu, 2017) pathologies.
Estrogen affects mitochondria breathing chain through the estrogen
receptors and NRF1, and is an important cofactor of mitochondrial
antioxidant defense, and it is thought to be the main reason of relatively
higher lifespan in females (Viña et al., 2005). Estrogen levels’decrease
in women after menopause has significant deteriorating health effects
(Jones and Boelaert, 2015).
A number of mitochondrially addressed interventions may amelio-
rate aging-relation conditions.
Exercise (Wang et al., 2011), sildenafil(Li et al., 2018), quercetin
(Nieman et al., 2010) and epicatechin (Ramirez-Sanchez et al., 2013)
supplementation may improve mitochondrial biogenesis.
Nicotinamide riboside supplementation improves NAD + blood
levels (Airhart et al., 2017;Trammell et al., 2016;Yoshino et al., 2018),
while its clinical relevance is being investigated.
There is some promising evidence for a direct effect of the NAD+
precursor acipimox on muscle mitochondrial function in humans in-
cluding increased insulin sensitivity, and increased mitochondrial re-
spiration in skeletal muscles (van de Weijer et al., 2015). Additionally,
acipimox can reduce plasma glucose, improve blood lipid profile, pre-
vent cardiac parasympathetic modulation in hypopituitary men
(Vestergaard, 2017).
A number of antioxidant interventions are effective in reducing
mortality in some groups of patients, including glucosamine and
chondroitin (Katoh et al., 2017), CoQ10 (Alehagen et al., 2018), pen-
toxifylline (McCarty et al., 2016), NAC (Darweesh et al., 2017), mela-
tonin (Raygan et al., 2017), edaravone (Okada et al., 2018), SGLT2
inhibitors (Fatima et al., 2017;Shigiyama et al., 2017), anti-RAAS drugs
(Baykal et al., 2003), curcumin (Tabrizi et al., 2018b), resveratrol
(Tabrizi et al., 2018a) and olive oil phenols (Fabiani, 2016). Melatonin
reduces cancer mortality (Seely et al., 2012).
Other promising anti-oxidant interventions include MitoQ (Rossman
et al., 2018), carnosine (Regazzoni et al., 2016), and the intake of
polyphenols like flavonoids, such as quercetin (Askari et al., 2012),
procyanidins (Li et al., 2015), and stilbenes (Reinisalo et al., 2015).
Coffee consumption (Martini et al., 2016), vitamin D (Farrokhian et al.,
2017), S-adenosylmethionine (SAMe) (Loguercio et al., 1994), gluco-
samine (Katoh et al., 2017) also have antioxidant effects. Statin use has
ambivalent effects on mitochondrial metabolism (Bouitbir et al., 2012).
Interestingly, mitochondrial transplantation has not only shown
promising results in animal studies, but also has been used in humans to
improve assisted reproduction outcomes (Woods and Tilly, 2015).
3.2.7. Insulin resistance
Regulation of cellular glucose and other nutrient metabolism is
necessary for organismal functionality (López-Otín et al., 2013).
Insulin resistance (IR) plays a major role in critical health condi-
tions, such as inflammation and starvation. However, impaired insulin
sensitivity is a major hallmark and an early sign of aging (Belsky et al.,
2015).
IR is a pathological condition in which cells fail to respond to insulin
normally. Significant number of middle-aged and older adults have
diabetes or prediabetes (Yip et al., 2017). IR is associated with higher
risks of cardiovascular, kidney diseases and all-cause mortality (Chan
et al., 2017;Huang et al., 2016b). Diabetes is associated with increased
risks of diabetic nephropathy, diabetic retinopathy, cognitive decline
(Cheng et al., 2012), dementia, mobility decline, falls (Lu et al., 2009),
and some cancers (Xu et al., 2017;Zhang et al., 2017). It is char-
acterized by impaired glucose utilization, high blood sugar, increased
lipolytic activity in fat cells, circulation of FFAs and inappropriate ac-
cumulation of lipids, including abdominal and liver fat.
Chronic β-cells exposure to FFAs may lead to the loss of insulin
response by β-cells, which eventually may become permanent
(Mookerjee et al., 2010).
A number of factors are associated with IR, including inflammation
(Park et al., 2014), pro-fibrotic signaling (Lark and Wasserman, 2017),
oxidative stress (Drougard et al., 2015), exposure to ectopic lipids such
as FFAs and to some misfolded proteins (Blaise et al., 2013;Singh et al.,
2015;Taylor et al., 2015). Excess body weight, lipid accumulation in
insulin-targeted organs including skeletal muscles and liver, and hor-
monal aging are all associated with IR, which can be exacerbated by
suboptimal diet, inactivity and a sedentary lifestyle (Shulman, 2014),
but also with inflammation (Park et al., 2014) and the history of mal-
nutrition (Francis-Emmanuel et al., 2014). Dysfunctions of hypotha-
lamic tissues (Drougard et al., 2015), as well as dysregulated adipokine
signaling (Jaganathan et al., 2018) play major roles in IR development.
In fact, IR promotes LDL resistances (via proprotein convertase
subtilisin/kexin type 9 (PCSK9)-centered pathways which involves
sterol regulatory element-binding transcription factor 1 (SREBP1),
glucokinase, and hepatocyte nuclear factor 1 (HNF1)) (Miao et al.,
2015;Wiciński et al., 2017;Zhang et al., 2016). Similarly, impaired
fatty acid beta-oxidation is associated with IR.
Fatty acid resistance (inadequate fatty acid beta-oxidation) can be
triggered by overfeeding, aging-related mitochondrial, adipocyte and/
or hepatocyte dysfunction, as well as by IR (Kim et al., 2006). This
results in the elevated plasma FFA levels commonly seen in aging
(Pararasa et al., 2015). Increased systemic FFA levels (saturated FFAs in
particular) increases the risks of all‐cause and cardiovascular mortality
and diseases, such as NASH and NADFL, as well as high blood pressure,
impaired endothelial cell function, increased inflammatory markers,
mitochondrial aging (Gaddipati et al., 2010;Pararasa et al., 2015) and
renal fibrosis (Kang et al., 2014). Fatty acid resistance involves (in
addition to IR) altered signaling of adipokines (Jura and Kozak, 2016),
peroxisome proliferator-activated receptor δ(PPARδ), pyruvate dehy-
drogenase lipoamide kinase isozyme 4 (PDK4) (Kim et al., 2006), solute
carrier family 13 member 5 (mINDY) (Rogina, 2017), FAT3, CD36, and
long-chain fatty acyl-CoA (LCFA-CoA) (Pararasa et al., 2015).
Elevated plasma triglycerides can result from overeating, IR, general
lipid abundance in the organism and high FFA levels (Welty, 2013).
Hypertriglyceridemia is involved in the development of NASH (Amir
and Czaja, 2011) and pancreatitis, and is associated with increased risks
of cardiovascular and all-cause mortality (Liu et al., 2013).
Resistance to the anabolic action of insulin and increased adiposity
are directly and mechanically involved in anabolic resistance, i.e. aging-
associated decrease in protein synthesis in the presence of adequate
amount of protein in food, which results in muscle loss and sarcopenia
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
7
in older people. Major factors of anabolic resistance include aging, in-
activity, obesity (Smeuninx et al., 2017), IR (Cleasby et al., 2016), and
inflammation (Xia et al., 2017).
Therefore, progressive resistance to many essential nutrients such as
glucose, lipids and proteins is observed in aging, which is more pro-
minent in inactive or obese older individuals. IR plays a major role in
this impaired nutrient sensing.
A number of interventions can improve IR providing major health
benefits, including exercise (Conn et al., 2014), avoiding prolonged
sitting (Benatti and Ried-Larsen, 2015), weight loss (Houmard et al.,
2002) and weight-loss inducing interventions (Khera et al., 2018;
Silvestre et al., 2018), healthy diets (Schwingshackl et al., 2018a,
2017a), consumption of olive oil (Schwingshackl et al., 2017b), whole
grains (Marventano et al., 2017), nuts (Kim et al., 2018c) and coffee as
well as supplementation with polyphenols, including flavonols
(Menezes et al., 2017) and anthocyanins (Yang et al., 2017).
Some antidiabetic medications significantly reduce all-cause and
cardiovascular mortality in people with diabetes, including metformin
(Haukka et al., 2017), glucagon-like peptide-1 (GLP-1) agonists, SGLT2
inhibitors (Fatima et al., 2017). In fact, metformin use is also associated
with cancer-specific mortality reduction (Haukka et al., 2017).
A number of anti-glycemic interventions decreases not only plasma
glucose but also triglyceride or FFA levels (Rosenblit, 2016), for ex-
ample, metformin reduces the levels of plasma FFAs (Castro Cabezas
et al., 2012).
Other anti-glycemic and anti-triglyceridemic interventions include
acipimox (Makimura et al., 2016), ginger (Mazidi et al., 2016), pro-
biotics (Kasińska and Drzewoski, 2015;Wu et al., 2017), berberin (Lan
et al., 2015a), vitamin D (Jafari et al., 2016;Poolsup et al., 2016), olive
leaf extract (de Bock et al., 2013;Lockyer et al., 2017), magnesium
(Verma and Garg, 2017), sildenafil(Ramirez et al., 2015), melatonin
(Doosti-Irani et al., 2018), fenugreek (Gong et al., 2016), Salacia
(Jeykodi et al., 2016), Tribulus Terrestris (Samani et al., 2016), As-
tragalus (Tian et al., 2016) and carnosine (de Courten et al., 2016;
Menon et al., 2018).
3.2.8. Aging-related body composition changes
Aging in humans is associated with a decreased share of lean mass
and an increased share of fat body mass, adipose tissue expansion, and
ectopic fat deposits in visceral area, muscles, heart, blood vessels, bone
marrow, liver, and pancreas.
The decline in non-fat cell mass in aging goes together with de-
creased mass of muscles, spleen, liver, kidney, brain, and bones
(Manini, 2010). Lung volume and functionality is decreased in older
ages (Koch et al., 2011).
Age-related decline in maximal oxygen uptake (VO2max) results
from multiple factors: decreased maximal heart rate and stroke volume,
stiffening heart muscle fibers, reduced muscle volume and strength, and
as well as diminished blood volume (Kim et al., 2016a).
Skeletal muscle mass usually contributes up to about 50% of total
body weight in young adults in high-income societies and decreases
during aging to approximately 25% of total body weight by 75–80 years
(Short et al., 2004), Skeletal muscle loss has major negative impact on
indicators of whole body mitochondrial capacity, VO2max (Coen et al.,
2013;Mathers et al., 2012) and resting metabolic rate (RMR). Skeletal
muscle loss was detected in both aged untrained individuals and pro-
fessional athletes (Kusy and Zieliński, 2014), but it is greatly ex-
acerbated by low physical activity.
Modern humans evolved from hunting and gathering societies,
where people were used to very high physical activity levels throughout
old age. Traditional farmers also have rather high physical activity
compared to modern office workers. Food has never been as abundant
as in the last few decades in the developed countries, and human brains
are not fitted for rigorous appetite control, as our ancestors had to
survive through persistent risks of malnutrition and frequent famines.
As a result, humankind faces new challenges with detrimental health
effects of sedentary lifestyle and obesity (Kirchengast, 2014).
Additionally, aging-related muscle loss is mediated by IR, anabolic
resistance, epigenetic reprogramming, and mitochondrial dysfunctions
including Complex I dysfunction, reduced ATP synthesis (Su et al.,
2015), reduced muscle oxygen consumption (Coen et al., 2013), in-
creased ROS signalling (Doria et al., 2012), diminished Na/K-ATPase,
as well as anabolic hormone signalling, muscle denervation (Spendiff
et al., 2016), and muscle fibrosis due to TGF-β1and myostatin signal-
ling (Parker et al., 2017).
Reduced volume of skeletal muscles and diminished lung function
affect each other negatively during aging (Koch et al., 2011). Numerous
population studies have documented an inverse association between
lung volume markers (VO2max, forced expiratory volume in 1 second
(FEV1)) and aging-related endpoints including all-cause and cardio-
vascular mortality, cognitive functions, T2D (Zaccardi et al., 2015), and
fractures (Kim et al., 2018c;Mathers et al., 2012).
In addition to decreased oxygen demand, lung volume can be ne-
gatively affected by thoracic cage stiffening from rib cage calcification,
age-related kyphosis from osteoporosis, persistent low-grade in-
flammation, proteolytic and oxidant-mediated injury to the lung matrix
resulting in the loss of alveolar units, elastin loss, as well as with im-
mune senescence and loss of lung stem cell regenerative capacity
(Brandenberger and Mühlfeld, 2017).
Aging-related loss of lean body mass can result in either body mass
loss or increased share of adipose tissue. Both obesity and being un-
derweight are associated with increased risks of all-cause mortality,
with low body weight being particularly dangerous in older adults
(Global BMI Mortality Collaboration et al., 2016).
Diminishing energy expenditures, RMR and physical activity levels
lead to lower energy demand. On average, people decrease their caloric
consumption during aging, which increases the risks of nutritional de-
ficiencies in old age (Giezenaar et al., 2016). Many aging individuals,
however, do not adjust their caloric consumption to decreased energy
demands which results in weight gain.
Age-associated weight gain is a well documented phenomenon ty-
pically associated with aging through middle ages (Belsky et al., 2015).
Obesity itself has been shown to lead to the various forms of cellular
and tissue dysfunctions characteristic of aging, and is associated with
an increased risk of comorbidities, including diabetes, CVDs, stroke,
cancer, liver diseases, osteoporosis, osteoarthritis, and depression
(Abdelaal et al., 2017).
At the same time, aging-related increase in adiposity is causally
implicated in age-related inflammation, due to inflammatory marker
overexpression in obese individuals (Hotamisligil et al., 1997;Weisberg
et al., 2003). Similarly, aging-related weight gain and obesity are the
major factors of IR, leading to further weight gain and insulin in-
sensitivity (Pararasa et al., 2015).
A large share of the middle-aged and older overweight individuals
persistently try, but fail to control their appetite and food consumption,
which might be aggravated by aging-related conditions such as IR,
adipokine signalling changes, as well as by reduced signalling of neu-
rotransmitters, including dopamine and gamma-Aminobutyric acid
(GABA) (Delgado, 2013). Uncompensated overeating is the major
source of aging-related weight gain and obesity.
Eating behavior and physical activity are influenced by various
neurotransmitters and changes in their metabolism in aging. Aging-
related decline in physical activity is detrimental to both muscle ca-
pacity and insulin tolerance. It is observed not only in older humans,
but also in other species. It is determined by aging-related changes in
neurotransmitter signalling, including orexin, dopamine, and agouti-
related protein (AGRP) (Knab and Lightfoot, 2010;Manini, 2010;
Ruegsegger and Booth, 2017).
Similarly, hormones and other neurotransmitters have major effects
on appetite and the ability to control food intake, including insulin
sensitivity mediator signalling, such as adipokines (Koleva et al., 2013),
dopamine, GABA (Delgado, 2013), neuropeptide Y, AGRP (Ferrario
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
8
et al., 2016), brain-derived neurotrophic factor (BDNF), ciliary neuro-
trophic factor (CNTF), α-melanocyte-stimulating hormone (α-MSH),
and a lot of these signals are diminished or altered in aging (Xu and Xie,
2016). Hypothalamic gliosis and TGF-βsignalling is associated with IR
and obesity, which implies the role of neurodegeneration in these
processes (Dorfman and Thaler, 2015;Schur et al., 2015).
Increased adipocyte volume in obese individuals is associated with
the inability to store triglycerides, impaired mitochondrial function,
alterations in membrane proteins and higher levels of adipocyte cell
death and inflammation, all of which have causal implications in the
development of obesity-related metabolic dysfunction (Heinonen et al.,
2014;Maurizi et al., 2018). Larger hypoxic areas of the adipose tissues
in combination with its increased proinflammatory microenvironment,
as seen in age-related increase in adiposity, is further aggravated by IR
(Cinti et al., 2005;Kovsan et al., 2011).
Aging promotes the shift from subcutaneous and lower body adip-
osity to visceral fat expansion, which has detrimental metabolic effects,
including inflammation, IR, cardiovascular diseases (Manini, 2010;
Pararasa et al., 2015) and NAFLD (Verrijken et al., 2010). Visceral
adipose tissue secretes more pro-inflammatory cytokines, promotes IR
with lower adiponectin signalling and leads to higher FFA plasma levels
due to its lower fat storing capacity compared to subcutaneous fat depot
(Manini, 2010;Pararasa et al., 2015). Enlarged visceral adipocytes are
associated with dyslipidemia (Hoffstedt et al., 2010).
Liver fat deposits are the main cause of NAFLD and NASH, con-
tributing to liver fibrosis and cirrhosis. Liver volume decreases by 20-
40% as a person gets old, predominantly due to functional cell loss (Kim
et al., 2015b). Major mechanisms linked to liver fat accumulation in-
clude cellular senescence, which leads to impaired liver regeneration,
obesity, inflammation, hypoxia, IR, and fibrosis (Pararasa et al., 2015).
Mitochondrial dysfunctions also promote the hepatic fat expansion,
including SIRT1 and NAMPT (Gaddipati et al., 2010) loss and oxidative
stress (Masarone et al., 2018). Toxicant exposure and fibrosis can lead
to reduced number and size of fenestrations (pores) of liver sinusoidal
endothelial cells. Liver defenestration may lead to an increase in liver
fat deposits and impaired lipid processing in the liver (Kim et al.,
2015b).
Overeating leads to increased plasma lipid levels, and together with
oxidative stress and inflammation promotes atherosclerosis develop-
ment.
Increased share of fat in bone marrow affects bone health negatively
leading to lower bone density with increased risks of osteoporosis and
vertebral fractures (Schwartz, 2015).
Physical activity, including aerobic and resistance exercise, is at
least partly capable of preventing and restoring aging-related loss of
muscle mass, energy expenditure (Siparsky et al., 2014), and VO2max
(Burtscher, 2013).
A number of nutritional supplements have been used to protect
muscle mass and function and promote physical activity and mobility in
older people, including vitamin D3 (Cleasby et al., 2016), higher caloric
content, amino acids, high protein content (Cawood et al., 2012), n-3
fatty acids (Bell et al., 2017), and β-Hydroxy β-Methylbutyrate (HMB),
a metabolite of leucine amino acid (Wu et al., 2015b). A high-protein
oral nutritional supplement with HMB reduced mortality among mal-
nourished, older, hospitalized adults (Deutz et al., 2016).
Testosterone supplementation for men alone or in combination with
human growth hormone (GH) might increase muscle mass and decrease
fat mass (Giannoulis et al., 2012). However, the safety of these ap-
proaches is still a major issue, as pro-anabolic signalling is implicated in
the development of aging-related diseases (for example, insulin-like
growth factor 1 (IGF-1) and mTOR signalling activated by GH, as well
as dihydrotestosterone, a testosterone metabolite, are involved in both
normal regenerative processes in neural or muscle tissues, but also in
aging and disease development (Saxton and Sabatini, 2017). Another
example is dehydroepiandrosterone (DHEA) supplementation, which
improves body composition in older men (Corona et al., 2013), but
whose safety is still not clear.
Certain diets can promote weight reduction in overweight in-
dividuals, including energy restriction, low-fat, low-carbohydrate,
Mediterranean (Mancini et al., 2016), and vegetarian (Huang et al.,
2016a) diets, nut and legume consumption (Schwingshackl et al.,
2018b). Exercise can also be effective for weight loss if combined with a
proper diet (Stoner et al., 2016).
A number of pharmacological interventions are effective at pre-
venting, slowing and reversing both weight-gain in general as well as
age-related weight gain. Some antidiabetic drugs (in addition to redu-
cing morbidity and mortality) are found to reduce body weight in
people with diabetes: metformin, acarbose, miglitol, pramlintide, ex-
enatide, liraglutide (Domecq et al., 2015). The use of liraglutide as an
anti-obesity agent is currently studied for long-term health effects
(Davies et al., 2018).
Resveratrol (Mousavi et al., 2018b), probiotics (Zhang et al., 2015),
curcumin (Mousavi et al., 2018a) and ginger (Maharlouei et al., 2018)
are somewhat effective for reducing IR and for weight loss, but re-
sveratrol use might increase LDL (Zhao et al., 2019a).
Bariatric surgeries provide major weight loss benefits and lead to
lower long-term all-cause cardiovascular and cancer mortality among
young and middle-aged adults with obesity (Cardoso et al., 2017).
Orlistat reduces fat absorption, and consequently, caloric con-
sumption. This results not only in weight loss, but also in improved
blood lipid profiles (Sahebkar et al., 2017).
A number of medicines lead to weight reduction as direct or side
effects, affecting neurotransmitters, such as dopamine, GABA, gluta-
mate, and serotonin: phentermine, zonisamide, topiramate, bupropion,
fluoxetine, phentermine, lorcaserin (Domecq et al., 2015). Long-term
safety of these agents remains to be explored. Phentermine/topiramate
controlled-release use was associated with weight loss, improved pa-
tients' lipid profiles, particularly their levels of triglycerides and HDL
cholesterol, insulin sensitivity and glycemia, retarded the progression of
T2D (Bays and Gadde, 2011;Kiortsis, 2013), but tended to increase
heart rates (Alfaris et al., 2015).
Statins significantly reduce not only cardiovascular risks but also
all-cause mortality in people with dyslipidemia (Naci et al., 2013). Yet,
statin use might cause myopathy as a side effect.
Lipid-lowering interventions with potential health benefits are
berberine (Lan et al., 2015b), flaxseed interventions (Pan et al., 2009),
consumption of ginger (Mazidi et al., 2016), olive products (Filip et al.,
2015), dietary flavonoid intake (Menezes et al., 2017), and policosanol
(Gong et al., 2018).
3.2.9. Aging-related hormonal changes
Hormone profiles change significantly in aging humans, and many
of these changes are clinically significant, leading to health impairment
and frailty.
Aging brings reduced production of sex hormones, which leads to
physiologic changes: reduced muscle mass, energy, and exercise capa-
city, bone loss, increased risks of AD (Jones and Boelaert, 2015;Uchoa
et al., 2016) and decline in sexual function (Williams and Cho, 2017).
Aging-related estrogen loss is especially pronounced in women after
menopause, which has direct detrimental health effects. Estrogen re-
ceptors are important transcriptional factors regulating pathways of
mitochondrial oxidative metabolism, which might partly explain lower
mortality in females compared to males (Austad and Fischer, 2016).
A later age of natural menopause (ANM) correlates with lower all-
cause mortality (2% with each increasing year of ANM), decreased risk
of CVD, atherosclerosis, stroke and osteoporosis (Schoenaker et al.,
2014). These benefits seem to outweigh side effects such as a moderate
increase in breast and ovarian cancer risks (Day et al., 2015;
Schoenaker et al., 2014). Menopause-related estrogen loss increases
cardiovascular risk factors, such as endothelial dysfunction, dyslipi-
demia, hypertension, IR, hypercoagulability, and pro-inflammatory
state. It also increases risks of osteoporosis (Jones and Boelaert, 2015),
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
9
and leads to changes in body composition, neurodegeneration (Uchoa
et al., 2016) and optic nerve aging (Dewundara et al., 2016).
Low levels of endogenous testosterone in older men are associated
with increased risks of all-cause and cardiovascular mortality (Araujo
et al., 2011) and AD (Lv et al., 2016), as well as higher fat mass (Bann
et al., 2015), metabolic syndrome, diabetes, dyslipidemia, hyperten-
sion, renal failure, frailty, malignancy and cardiovascular events
(Shores and Matsumoto, 2014).
The blood levels of DHEA and its metabolite dehydroepian-
drosterone sulfate (DHEAs) decrease in aging. Low DHEA and DHEAs
levels in older people are associated with increased risks of mortality
(Rosero-Bixby and Dow, 2012), frailty (Tajar et al., 2011), depression,
T2D and AD (Jones and Boelaert, 2015).
In summary, reduced sex hormone metabolism is associated with
generally poorer health in aging individuals.
Aging influences many aspects of complex hormonal system. The
cells and tissues of the neuroendocrine glands, including hypothalamus,
a brain structure that controls the other structures in the endocrine
system, are affected by aging-related neurodegenerative processes.
In turn, neural aging is driven by pathological processes like neu-
roinflammation, microglia excessive activation, cellular senescence
(Ojo et al., 2015), mitochondrial dysfunction, oxidative stress, ac-
celerated neuronal apoptosis, impaired neurogenesis, neurovascular
aging, gliosis, and IR (Hardeland et al., 2015;Yin et al., 2016). Im-
paired proteostasis, including impaired amyloid processing, exacer-
bates neural aging, including the aging of neuroendocrine organs re-
ducing brain neurosteroid synthesis among other things (Barron and
Pike, 2012).
There is preclinical data that inflammatory signalling, such as TNF-
α, inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-β) and
NF-κB, impairs hypothalamic neurogenesis leading to aging-related
decline in gonadotropin-releasing hormone (GnRH) signalling (Zhang
et al., 2013). Hypothalamic gliosis is associated with IR and obesity
(Schur et al., 2015), which could be signs of inflammatory response
(Dorfman and Thaler, 2015;Schur et al., 2015). Hypothalamic aging
results in decrease and dysregulation of GnRH pulsations (Veldhuis
et al., 2009;Zhang et al., 2013), which can be detrimental for sex
hormone metabolism. In fact, about 85% of male hypogonadism cases
are secondary in the sense that the testes are being insufficiently sti-
mulated by the hypothalamic-pituitary axis (McCullough, 2015).
Also, neurodegeneration of hypothalamic suprachiasmatic nucleus
is involved in reduced melatonin metabolism, which causes sleep dis-
turbances and deprives aging human organisms of multiple benefits of
melatonin, including anti-inflammatory and antioxidant defense and
bone health support (Hardeland et al., 2015). In addition, the size of
melatonin-producing pineal gland decreases in aging.
At the same time, human gonads (testes and ovaries) are affected by
aging as well. Aging testicular tissues undergo volume loss, IR, oxida-
tive stress, vascular dysfunctions, hypoxia and fibrosis. Testosterone-
producing Leydig cells suffer from mitochondrial dysfunction and oxi-
dative stress resulting in reduced steroidogenesis (Wang et al., 2017).
They decrease in quantity, which plays a role in aging-related reduction
in androgen levels (Gunes et al., 2016).
Menopause involves follicular dysfunctions and depletion, as well as
hypothalamic function alterations. The number of primordial follicles
rapidly declines with time. About 1 million oocytes are present at birth
in the human ovary, about 400,000 follicles are present at puberty, and
only about 500 (about 0.05%) ovulate, while the rest are wasted
(Wilkosz et al., 2014).
Decreased number and function of follicular granulosa cells results
in decreased estrogen and inhibin B secretion. This leads to increased
GnRH and follicle-stimulating hormone (FSH) secretion during early
stage of menopause (Harlow et al., 2012). Additionally, the signaling of
hypothalamic GnRH-promoting peptide kisspeptin is significantly in-
creased with women’s age which accelerates menopause (Day et al.,
2015). FSH promotes growth and recruitment of immature ovarian
follicles, which ultimately accelerates their depletion, leading to me-
nopause (Day et al., 2015).
Primordial and small follicle loss with aging results in the loss of
inhibin B and Anti-Müllerian hormone, as they are secreted by smaller,
less developed follicles (Rojas et al., 2015). This results in accelerated
oocyte development to a more mature state which makes them more
prone to apoptosis and follicular atresia. Depletion of follicles leads to
significant decrease in androgen and estrogen production, declining
fertility and ultimately menopause. GnRH secretion is diminished
during late postmenopause (Harlow et al., 2012).
Oocytes suffer from reduced oxidative defense, mitochondrial dys-
functions, telomere attrition, lipotoxicity (Diamanti-Kandarakis et al.,
2017;Keefe et al., 2015), AGEs, and DNA damage (Wilding, 2015).
Ovarian DNA damage repair system deteriorates with age, as its prin-
cipal agent breast cancer type 1 susceptibility protein (BRCA1) is pro-
gressively lost in aging (Oktay et al., 2015) which is related to meno-
pause (Day et al., 2015). Additionally, ovarian stromal cells and
adjusting tissues undergo cellular senescence which leads to increased
inflammatory signalling, tumorigenic propensity (Shan and Liu, 2009),
and ovarian stromal fibrosis (Briley et al., 2016).
Testosterone replacement therapy improves health, quality of life
and reduces all-cause mortality in men with hypogonadism (Hackett,
2016). It has benefits in terms of sexual and physical functioning, mood,
and depressive symptoms, however, its long-term safety needs to be
evaluated in large clinical trials (Snyder et al., 2016). At the same time,
recreational anabolic steroid use by young men leads to prolonged
decrease of endogenous serum testosterone levels (Christou et al.,
2017). There is early clinical data on hypogonadism treatments, cap-
able of restoring endogenous testosterone production in men, including
human chorionic gonadotropin, clomiphene citrate, and some ar-
omatase inhibitors (McCullough, 2015).
Certain preparations of HRT may provide significant symptom-re-
ducing benefits for younger healthy postmenopausal women (50–60
years old). The benefits include a reduction in all-cause mortality,
coronary health disease and osteoporotic fractures. At the same time,
certain HRT regimes can increase risks of breast, ovarian and uterine
cancers, and thrombotic events, which limits HRT use (Lobo, 2017).
Further clinical studies are needed.
Nulliparity, vegetarian diet, smoking, high polyunsaturated fat in-
take, and excessive exercise consistently correlate with earlier age at
natural menopause. Higher BMI, higher intake of total fat, protein, and
meat, dietary vitamin D and calcium intake, as well as moderate phy-
sical activity and exercise delay the age at natural menopause (Sapre
and Thakur, 2014).
Coenzyme Q10 supplementation might preserve female fertility, but
further research is needed (Gretchen Garbe Collins, 2015).
3.2.10. Cardiovascular aging
Cardiovascular diseases (CVDs) are a major cause of aging-related
morbidity and mortality. Ideal cardiovascular health metrics are asso-
ciated with a 46% lower all-cause mortality compared to people with
the worst indicators (Guo and Zhang, 2017).
By delivering oxygenated blood to all tissues in the body, the car-
diovascular system plays a vital role in the health and longevity of the
organism as a whole. Accumulation of cardiovascular system dysfunc-
tions can make cardiovascular system a major driver of pathological
processes in an aging individual. Therefore, we denote cardiovascular
aging as a separate and major causal process in aging pathogenesis.
Thus, peripheral artery disease can lead to stroke, renovascular
hypertension, renal dysfunctions, mesenteric ischemia, ischemia in
lower and upper extremities (Aboyans et al., 2018). Cerebrovascular
dysfunctions are major risk factors for stroke, dementia, cognitive de-
cline, and neural aging (Toth et al., 2017). Vascular aging and diseases
are involved in the pathogenesis of eye diseases, including macular
degeneration, Schnabel cavernous degeneration, and possibly, presby-
opia (Pescosolido et al., 2016), as well as loss of hearing (Kurata et al.,
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
10
2016) and taste sensitivity (which could lead to malnutrition in old age)
(Pavlidis et al., 2013). Microvascular damage is involved in many pa-
thological processes, including neural, myocardial, lung, kidney, colon,
skin (Ambrose, 2017), and tendon aging (McCarthy and Hannafin,
2014). Also, vascular damage is a major cause of erectile dysfunction
(El-Sakka, 2011).
Aging has a remarkable effect on the heart and vascular system,
leading to the increase in CVD incidence including ischemic heart dis-
ease, atherosclerosis, hypertension, heart failure, myocardial infarction,
and stroke. Cardiovascular fitness (measured, for example, by VO2max)
declines in aging adults, especially in people with low physical activity
(Burtscher, 2013).
Cardiac and vascular, in particular, arterial wall remodeling, stif-
fening and fibrosis seem to be major processes contributing to aging
pathogenesis as a whole. Vascular remodelling sincludes irreversible
degradation of elastic fiber in the blood vessel walls, collagen deposi-
tion and cross-linking, blood vessel wall thickening, amyloid deposition
in the medial layer, and migration/proliferation of vascular smooth
muscle cells to the intima. Heart aging can be exacerbated by left
ventricular (LV) hypertrophy, altered LV diastolic function, diminished
LV systolic reserve capacity, increased arterial stiffness, impaired en-
dothelial function and cardiac rhythm disturbances (North and Sinclair,
2012). Cardiovascular aging is exacerbated by hypertension, dyslipi-
demias, ischemia, reduced vascular perfusion (Ungvari et al., 2018),
and altered noradrenergic vascular innervation (Hunter et al., 2012).
It is clear that low physical activity greatly contributes to en-
dothelial dysfunction and aggravates cardiovascular aging (de Almeida
et al., 2017). There is evidence of people from a few modern hunter-
gatherer and forager-horticulturalist societies having unusually low
prevalence of atherosclerosis implying a major role of lifestyle in car-
diovascular aging (Kaplan et al., 2017;Lemogoum et al., 2012).
Both menopause and hypogonadism have particular detrimental
effects on cardiovascular health (Jones and Boelaert, 2015).
The pathological processes of cardiovascular aging are driven by
mechanical stress in the blood vessel walls, exacerbated by hyperten-
sion and RAAS activation, pro-inflammatory, pro-fibrotic (TGF-β) and
proteolytic (MMP-12) signalling, cellular senescence, mitochondrial
dysfunction, IR, immune senescence (Yu et al., 2017), as well as by
misfolded proteins such as amyloids, AGEs, AOPPs, and elastin peptides
(Hunter et al., 2012;Ungvari et al., 2018).
Pathogenesis of atherosclerosis involves dysregulated cholesterol
metabolism, oxidation of TG-rich lipoproteins, cellular senescence, in-
flammation (IL-1, TNF-α, IL-6 pathways) (Ridker and Lüscher, 2014),
and mitochondrial dysfunctions (Ungvari et al., 2018). Dysfunctional
calcium signalling may lead to both excessive cellular apoptosis and
blood vessel calcification. Vitamin D deficiency is associated with
higher all-cause, cardiovascular and cancer mortality, respectively
(Chowdhury et al., 2014).
Dysregulation of nitric oxide (NO) synthesis and processing occurs
with age and in the context of CVDs due to inflammation and oxidative
stress (Ungvari et al., 2018).
A number of interventions are effective for primary or secondary
prevention of cardiovascular aging, diseases, as well as of cardiovas-
cular and all-cause mortality.
Physical activity and exercise, as well as reducing daily sitting time,
have major potentials in primary and secondary prevention of CVDs
(Alves et al., 2016), and some cancers (Kruk and Czerniak, 2013).
Healthier dietary patterns are associated with decreased cardio-
vascular and all-cause mortality, including whole-grain food, fruit, ve-
getable, nut, legume, and fish consumption, certain polyphenols (Kim
et al., 2018c;Rienks et al., 2017), moderate coffee intake (Zhao et al.,
2015), and possibly olive oil (Schwingshackl and Hoffmann, 2014).
Excessive consumption of red meat, especially processed meat, and
sugar-sweetened beverages have negative health effects (Bechthold
et al., 2017;Schwingshackl et al., 2017c). Similar associations are ob-
served for cancer risks (Bella et al., 2017).
Anti-hypertensive drugs reduce not only blood pressure, but also all-
cause mortality, CVD events, stroke, and heart failure in people with
hypertension (Ettehad et al., 2016), as well as retinopathy progression
(Xie et al., 2016).
Statin use in people at increased CVD risks (Chou et al., 2016), as
well as the use of some antidiabetic medications in people with T2D
(Haukka et al., 2017), such as metformin (Campbell et al., 2017), GLP-1
agonists and SGLT2 inhibitors reduce cardiovascular and all-cause
mortality (Fatima et al., 2017). Statin use might also decrease some
(Mei et al., 2017) cancer risks. Certain preparations of hormone re-
placement therapy, including parenteral estrogen therapy for younger
postmenopausal women (Lobo, 2017), as well as, possibly, long-acting
testosterone injection supplementation for men with hypogonadism
(Hackett, 2016) reduce cardiovascular and all-cause mortality.
Some anti-inflammatory treatments reduce both cardiovascular and
all-cause mortality, including aspirin (Sutcliffe et al., 2013). Glucosa-
mine and chondroitin supplementation, in addition to being used as
anti-osteoarthritic remedy, is associated with reduced all-cause, cardi-
ovascular, cancer and respiratory mortality (Bell et al., 2012) as well as
possibly colorectal (Ibáñez-Sanz et al., 2018;Kantor et al., 2016) and
lung cancer (Brasky et al., 2011) incidence. Glucosamine use might also
improve endothelial function (Katoh et al., 2017).
Bisphosphonate use improves calcium metabolism and may reduce
cardiovascular, all-cause and cancer mortality in patients with osteo-
porosis (Kranenburg et al., 2016;Van Acker et al., 2016), although the
effect on all-cause mortality was recently challenged (Cummings et al.,
2019). Some data suggests that low dose vitamin D3 supplementation
without calcium might reduce blood pressure (Golzarand et al., 2016),
but there is currently not enough data supporting cardioprotective ef-
fects of vitamin D supplementation to make any strong conclusions,
partly due to the lack of clinical trials in people with vitamin D defi-
ciency with regular administration of various doses of vitamin D3, and
not combined with calcium. At the same time, cohort studies of Swedish
women (Yang et al., 2011), as well as of some patient groups (Ho et al.,
2014;Shapiro et al., 2014) imply that sun exposure can be protective
against cardiovascular and all-cause mortality, as well as some aging-
related diseases, despite the increased skin cancer incidence (Hoel
et al., 2016;Lindqvist and Landin-Olsson, 2017).
High dietary magnesium intake is associated with lower cardio-
vascular and all-cause mortality (Fang et al., 2016). Magnesium affects
homeostasis of both calcium and vitamin D. There seems to be an op-
timal ratio between calcium and magnesium intake, and suboptimal
levels of this ratio (Rosanoffet al., 2016) disturb metabolism and ac-
celerate certain aging-related diseases. Magnesium supplementation
may decrease CVD risk factors (Verma and Garg, 2017).
CoQ10 supplementation decreased mortality and improves exercise
capacity in patients with heart failure (Li and Yan, 2017). NAC may
significantly ameliorate the consequences of myocardial Infarction
(Pasupathy et al., 2017).
Interventions boosting cyclic adenosine monophosphate (cAMP), an
ATP derivative, including PDE inhibitors including PDE5 inhibitors
(Andersson et al., 2017;De Vecchis et al., 2017), pentoxifylline
(Champion et al., 2014) and coffee intake (Poole et al., 2017;Zhao
et al., 2015), compensate for ATP deficiencies and could reduce car-
diovascular and all-cause mortality at least in some groups of people.
3.2.11. Other mechanisms of aging
Aging is obviously not confined to the pathological processes de-
scribed above. We identified several other mechanisms of aging
throughout the course of our research literature review.
This includes DNA damage, including DNA lesions such as muta-
tions, translocations, chromosomal gains and losses, telomere short-
ening, and gene disruptions caused by the integration of viruses or
transposons (López-Otín et al., 2013). DNA damage has clinically im-
portant effects in many types of aging cells and tissues, including stem
cells (Franco et al., 2018;Jaiswal et al., 2017;Weakley et al., 2010), as
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
11
well as oocytes (White and Vijg, 2016) and spermatozoa (Gunes et al.,
2016) contributing to aging-related fertility loss. DNA damage is a
major cause of cancer and in some cases of CVD (Jaiswal et al., 2017)
development.
Aging-related epigenetic changes are also a major issue affecting
directly or indirectly every hallmark of aging. This includes hetero-
chromatin loss, the formation of senescence-associated hetero-
chromatin foci, changes in global DNA methylation, histone loss and
histone code modifications, and alterations in biogenesis and functions
of non-coding RNA (Gangisetty et al., 2018;Pal and Tyler, 2016).
Changes of calcium metabolism in aging seem to be an important
albeit a complex (Cohen et al., 2018) issue as a number of interventions
improving calcium metabolism reduce all-cause mortality in aged
people (Fang et al., 2016;Golzarand et al., 2016;Kranenburg et al.,
2016;Van Acker et al., 2016). Aging-related pathologies include cal-
cium bone loss in osteoporosis, and vascular calcification, which are
correlated, at least in women (Zhang and Feng, 2017). On the other
hand, dysregulated calcium signalling is implicated in neurodegenera-
tive diseases of aging (Pchitskaya et al., 2018).
Finally, in addition to cardiovascular aging, aging of some other key
body organs and systems can drive the cascades of pathological pro-
cesses in organism as a whole. This includes aging-related damage to
liver, kidney, and nervous system. Similarly, stem cell exhaustion in
aging is another important issue driven by mitochondrial dysfunctions
(Zhang et al., 2018a), cellular senescence (Sui et al., 2016), DNA da-
mage (Beerman et al., 2014;Jaiswal et al., 2017), epigenetic changes,
as well as negative changes in the stem cell niches, including pro-in-
flammatory signalling and ROS (Chen et al., 2017a).
Yet, the complexity of aging does not seem to be indefinite, as it can
be described in terms of a number of pathological processes, which can
be in many cases addressed therapeutically to the overall benefit of the
patient.
We mapped connections between the major clinically significant
pathogenetic processes of aging in humans identified in this article from
the current medical research literature which we described in the ear-
lier sections of the article (Fig. 1).
3.3. Course and outcome: a distinct pattern of development over time
Aging-related pathologies are of chronic nature. They may be alle-
viated but they do not vanish in their complexity. Many biomarkers
change consistently as people age, but some have non-linear relation-
ships with calendar age (Yashin et al., 2010) due to changes in nutrient
sensing described above. These changes in metabolism and pharmaco-
dynamics are clinically important factors that can be used to identify
specific stages of aging, which might include aging in young adults (25-
40 y.o.) (Belsky et al., 2015), middle-aged (40-60 y.o.), youngest old
(60-69 y.o.), oldest old (80 years and older) (Forman et al., 1992),
(Lehallier et al., 2019), as well as centenarians and supercentenarians.
Aging may ultimately result in death even in the absence of major
underlying diseases (causes of death). At least some centenarians die
without specific major diagnosed diseases as underlying causes of death
(Bernstein et al., 2004;Meslé and Vallin, 2017). About 10% of super-
centenarians survive until the last 3 months of life without major age-
related diseases (Andersen et al., 2012). For many of centenarians old
age or senility (Chen et al., 2019;Evans et al., 2014;Meslé and Vallin,
2017) was recorded as the underlying cause of death which may be
explained by the combined effects of aging-related deficits leading to
general health deterioration in this group (Chen et al., 2019;Evans
et al., 2014;Meslé and Vallin, 2017). This adds to the observation that
pathological effects of aging cannot be entirely explained by ill effects
of aging-related diseases.
3.4. Treatment response: a known pattern of response to interventions
We identified and described above a number of interventions which
can reduce the symptoms of the major aging-related pathological pro-
cesses. Some of them are also effective against aging-related diseases,
Fig. 1. The major pathogenetic processes of aging.
Note: the dotted lines reflect the relationships relevant for only some organs or body systems, while the solid lines mark the relationships relevant for human
organism in general.
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
12
Table 1
Interventions against aging-related pathological processes
Intervention Inflammation Cellular
senescence
Proteostasis
failures
Immune
senescence
Fibrotic
propensity
Mitochondrial
dysfunctions
Insulin
resistance
Body
composition
changes
Hormonal
changes
Cardiovascular
mortality
Cancer
mortality
All-cause
mortality
Physical activity + (+) + +* + + + (+)* + + +
Healthy diet + (+) + (+) +* + + + +- + + +
Olive products + (+) + + + + + +
Coffee + +* (+)* + + ∼++
Nuts +++ + ++
Legume ++ +
Whole-grain products ++
Flavonoid consumption + + (+)* (+) + + + (+) (+)
Magnesium intake + + (+*) +*
Vitamine D3 supplementation + + + + (+) + (+) + +
Sun exposure (+) +- (+)
Probiotics ++ ++
Aspirin ++* +* + +
Coenzyme Q10 + +* + +* +* +*
Acipimox +* + + + (+)
Quercetin + + (+)* (+)* (+) +
Resveratrol +++-
Astragalus / TA65 + (+) (+)*
Berberine ++
Carnosine ++*+* + +
N-acetylcysteine + + (+)*
Ginger +++
Turmeric, curcumin ++* + +
Drugs against specific conditions
Statins +* +* +* +- +-* + +* +*
Metformin ++* +*+- +++
SGLT2 inhibitors +* + + + + +
GLP-1 agonists ++*++++
RAAS blocking drugs +* +* + + +* + +
Glucosamine / chondroitin + + (+) (+)* (+)
Bisphosphonates (+)* +* (+*)
PDE5 inhibitors + + +* (+) + +*
Pentoxifylline +++ ++*
HRT for women +* + +* +-* +*
Testosterone supplementation
for men with
hypogonadism
+* +* +*
Melatonin +++ +
Bariatric surgeries for people
with obesity
++ +
Note:+–effective; - –harmful; (+) possibly effective; +* –effective in some groups of people; –* harmful in some group of people.
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
13
while some reduce all-cause mortality in large population groups
(Table 1).
Physical activity stands out as a nearly universal anti-aging cure, in
that it ameliorates most of the aging-related pathological processes
surveyed here (Alves et al., 2016;Arem et al., 2015;Duggal et al., 2018;
Kruk and Czerniak, 2013;Mundstock et al., 2015;Rahman and Adjeroh,
2019). Healthy diets (Bechthold et al., 2017;Mancini et al., 2016;Rafie
et al., 2017;Schwingshackl et al., 2018a,2018b,2017a,2017c;Soltani
et al., 2017), high in flavonoids (Kim et al., 2018c;Rienks et al., 2017),
olive oil (Schwingshackl et al., 2017b,2015;Schwingshackl and
Hoffmann, 2014), coffee (Liu et al., 2015;Martini et al., 2016;Poole
et al., 2017;Zhang and Zhang, 2018;Zhao et al., 2015), nuts (Kim et al.,
2018b), legumes (Schwingshackl et al., 2017c), whole grain products
(Marventano et al., 2017;Rienks et al., 2017) and magnesium (Fang
et al., 2016;Rosanoffet al., 2016;Simental-Mendia et al., 2017;Verma
and Garg, 2017). Vitamin D and magnesium supplementation in people
with such mineral deficiencies also seem to have broad-spectrum anti-
aging effects (Chowdhury et al., 2014;Farrokhian et al., 2017;
Mirhosseini et al., 2018).
Aspirin seems to be another anti-aging drug for the eligible patients
(Richman and Owens, 2017;Sutcliffe et al., 2013;Whitlock et al.,
2015).
A number of drugs need to be tested as promising anti-aging in-
terventions in large clinical trials.
CoQ10 ameliorates some aging-related pathological processes and
may improve survival in patients with heart failure (Alehagen et al.,
2018;Lehagen et al., 2018;Li and Yan, 2017;Zhai et al., 2017).
Therefore, it might work as an anti-aging drug, although more research
in people without heart failure is needed.
Some antidiabetic drugs, such as metformin (Castro Cabezas et al.,
2012;de Kreutzenberg et al., 2015;Domecq et al., 2015;Haukka et al.,
2017;Wu et al., 2015a), GLP-1 agonists (Fatima et al., 2017) and
SGLT2 inhibitors (Bekki et al., 2018;Fatima et al., 2017;Shigiyama
et al., 2017) provide anti-aging benefits and extend lifespan and
healthspan in people with diabetes and are tested for other conditions.
RAAS blocking drugs (Kim et al., 2016b;Wu et al., 2015a) act as anti-
aging interventions in patients with hypertension, but they are also
used against fibrotic diseases.
Statin use addresses some (but not all) pathological processes of
aging and reduces all-cause mortality, at least in some groups of people
(e.g. those with dyslipidemia) (Boccardi et al., 2013;Chou et al., 2014,
2016;Geifman et al., 2017;Kim et al., 2017;Li et al., 2017a;Naci et al.,
2013;Paradisi et al., 2012;Riekse et al., 2006;Smith et al., 2017).
The use of bisphosphonates improves survival in cancer patients
with benefits generally outweighing the risks (Van Acker et al., 2016),
and may reduce all-cause mortality in patients with osteoporosis
(Kranenburg et al., 2016) although this finding was challenges recently
(Cummings et al., 2019).
Pentoxifylline (a PDE-3 inhibitor) may have anti-aging properties
(Champion et al., 2014;Chen et al., 2017c;McCarty et al., 2016;Pollice
et al., 2001;Wen et al., 2017), but more clinical trials on different in-
dications are needed. Interestingly, PDE-5 inhibitors in addition to
treating erectile dysfunction might have anti-aging effects in people
with a number of aging-related conditions like T2D (Anderson et al.,
2016) and heart failure (De Vecchis et al., 2017).
Glucosamine and chondroitin use also seems to act as an anti-aging
compound in its users (people with osteoarthritis) (Bell et al., 2012;
Katoh et al., 2017;Navarro et al., 2015).
Other promising but less studied interventions include N-acet-
ylcysteine (Ahmadi et al., 2017;Chughlay et al., 2016;Firuzi et al.,
2011;Talasaz et al., 2014), carnosine and close compounds
(Babizhayev et al., 2012;Babizhayev and Yegorov, 2016;de Courten
et al., 2016;Hisatsune et al., 2016;Menon et al., 2018;Regazzoni et al.,
2016), melatonin (Akbari et al., 2018;Doosti-Irani et al., 2018;
Hardeland et al., 2015;Raygan et al., 2017;Seely et al., 2012), NAD-
inducing substances including acipimox (Airhart et al., 2017;Trammell
et al., 2016;van de Weijer et al., 2015;Yoshino et al., 2018), probiotics
(Kasińska and Drzewoski, 2015;Lei et al., 2017;Wu et al., 2017;Zhang
et al., 2015), as well as plant-based quercetin (Askari et al., 2012;Byun
et al., 2017;Justice et al., 2019;Khan et al., 2016;Mohammadi-Sartang
et al., 2017;Nenna et al., 2015;Nieman et al., 2010;Sahebkar, 2017;
Serban et al., 2016), resveratrol (Chilelli et al., 2016;Guo et al., 2017;
Mousavi et al., 2018b;Tabrizi et al., 2018a;Zhao et al., 2019a), ber-
berine (Lan et al., 2015a), ginger (Maharlouei et al., 2018;Mazidi et al.,
2016), turmeric and curcumin (Chilelli et al., 2016;Mousavi et al.,
2018a;Tabrizi et al., 2018b), astragalus (Dow and Harley, 2016;He
et al., 2013;Tian et al., 2016;Wu et al., 2009), and olive-based pro-
ducts (de Bock et al., 2013;Fabiani, 2016;Filip et al., 2015;Lockyer
et al., 2017;Menicacci et al., 2017).
Certain regimes of HRT for post-menopausal women and men with
hypogonadism might have anti-aging effects (Lobo, 2017;Marjoribanks
et al., 2017), but more research is needed. Bariatric surgeries may
prevent pathologies of aging in people with obesity (Cardoso et al.,
2017).
This list is obviously incomplete, and it can be completed in the
future as geroprotectors identified in animal models will be tested in
humans (Moskalev et al., 2017), as well as with new clinical studies of
other interventions. So far we can generally conclude that the rate of
human aging does respond to interventions, both in general population
and patients with certain diseases.
3.5. Linkage to genetic factors: e.g., genotypes, patterns of gene expression
So far, only a few gene variants consistently associated with long-
evity in different ethnic groups have been identified (Dato et al., 2019).
Many of them are related to aging-related pathological processes, in-
cluding APOE (proteostasis, lipid metabolism) (Deelen et al., 2019),
FOXO3A, G vs T alleles, rs2802292 (defense against oxidative stress,
telomere length (Davy et al., 2018), cell survival, cardiovascular health,
etc.), KLOTHO KL-VS (calcium homeostasis, insulin sensitivity)
(Revelas et al., 2018), CDKN2A/B (cellular senescence) (Deelen et al.,
2019), IL-6 (inflammation) (Deelen et al., 2019), and rs2149954 on
chromosome 5q33.3 (cardiovascular health) (Nygaard et al., 2017). The
role of other longevity-associated gene variants remains to be fully
understood, i.e. rs7676745, located on chromosome 4 near GPR78
(Deelen et al., 2019). Interestingly, growth hormone receptor exon 3
deletion is associated with longevity in men (Ben-Avraham et al.,
2017).
Studies in some specific groups reveal other interesting longevity
gene candidates potentially relevant for new therapy development.
Thus, a study of longevity among Amish community identified that
carriers of the null SERPINE1 allele had a longer lifespan (Khan et al.,
2017). Studies in California identified a relationship between longevity
and dopamine D4 receptor DRD4 gene (Grady et al., 2013;Szekely
et al., 2016) which may be due to neural system metabolism in old age
(Volkow et al., 2013).
Genetic studies of the multi-ethnic oldest-old populations reveal the
importance of DNA repair and proteostasis mechanisms which may be
encoded by different gene variants (Kim et al., 2018b).
Hopefully, further genetic research will identify more gene variants
related to longevity which will help to identify pro-longevity clinical
strategies.
Aging is associated with significant aging-related epigenetic
changes (de Magalhães et al., 2009;Gopalan et al., 2017;Jung et al.,
2019;Li et al., 2019;Pal and Tyler, 2016;Salas-Pérez et al., 2019), but
their clinical significance, as discussed earlier, remains currently to be
fully understood.
3.6. Linkage to interacting environmental factor
Environmental factors have large-scale effects on the rate of aging.
In fact, a safer environment with better food security and pathogen
D. Khaltourina, et al. Mechanisms of Ageing and Development 189 (2020) 111230
14
control has allowed modern humans to achieve higher life expectancy
levels than ever before.
A systematic review of behavioral and metabolic risk factors of
disability-adjusted years of life lost identified poor control of high
systolic blood pressure, high fasting plasma glucose, smoking and high
BMI as major risk factors globally, each of them being a significant
factor of accelerated aging as discussed above (GBD 2017 Risk Factor
Collaborators, 2018). In fact, smoking is a major risk factor of aging-
associated diseases, all-cause mortality (Mons et al., 2015) and ac-
celerated aging (Mamoshina et al., 2019).
Socioeconomic status is associated with higher life expectancy
(Stringhini et al., 2017). Also, education is negatively associated with
the risks of non-communicable diseases other than neoplastic diseases
(Smith et al., 2015).
Education, smoking, BMI, alcohol intake, and physical activity are
correlated with biomarkers of epigenetic aging (Fiorito et al., 2019).
Certain work conditions, such as night-shift work (Lin et al., 2015),
strenuous occupational physical activity (Coenen et al., 2018) or pro-
longed occupational sitting (Kikuchi et al., 2015) might impede health
and accelerate aging.
Environmental toxic pollution is associated with increased mortality
from aging-related diseases (Chowdhury et al., 2018;Pope et al., 2019).
Social engagement (Rico-Uribe et al., 2018), meaningful work, and
volunteering (Anderson et al., 2014;Rogers et al., 2016) are associated
with improved survival.
Characteristics of a neighborhood and built-in environment may
affect health in older ages (Malambo et al., 2016). A highly-walkable or
mountain environment predisposes individuals to physical activity and
longevity (Pes et al., 2013).
Therefore, aging can be attenuated, and healthy longevity main-
tained via various modifications of the environment through the life-
course.
4. Discussion
Our review is obviously not comprehensive and should be further
developed. However, it does represent the first systematic approach to
implementing aging in the ICD. Using the WHO’s criteria for disease
classification, we conclude that aging generally fits all of them, and
therefore can be considered a disease.
We identified pathogenetic processes common for aging of different
organs and systems of the human body, according to the current state of
medical research. The major ones include aging-related low-grade
systemic inflammation, replicative cellular senescence, proteostasis
failures, immunosenescence, mitochondrial dysfunctions, increased fi-
brotic propensity, insulin resistance, body composition changes and
hormonal changes in aging. Aging of some human body systems and
organs, including cardiovascular, gastroenterological, neural and
kidney aging, leads to the rise of secondary pathogenetic cascades of
aging which can harm the aging organism as a whole. These identified
pathogenetic processes affect many human body organs and systems.
We mapped connections between various pathogenetic processes of
aging which were described in the relevant sections of this study above
and summarized them in Fig. 1. The analysis of pathogenetic me-
chanisms of aging shows their high degree of interconnection, which
presents aging as a complex but a holistic process. Immune senescence
and some aspects of hormonal aging stand out to some extent as less
connected to other components of aging, which makes them less sus-
ceptible to therapeutic interventions.
Unlike some previous systematic studies of aging (de Grey and Rae,
2007;López-Otín et al., 2013), our review was almost completely
confined to human studies. Our results are rather similar to these au-
thors, which reflects growing understanding and consensus on the
mechanisms of aging within the scientific community. Interestingly, our
study has identified aging-related increased fibrotic propensity as an as-
yet unrecognized hallmark of aging, in addition to traditionally
suspected ones. We would also like to stress the importance of further
human studies of epigenetic aspects of aging, DNA damage, as well as
calcium metabolism in aging. Some important aspects of aging were not
well studied in detail in human studies and could be added to research
reviews on human aging in the future. We hope that future research on
aging will allow for the development of a more unifying framework that
can reduce fragmentation of the various approaches, indicators and
interventions.
A number of interventions were identified, including lifestyle
changes, approved drugs and supplements, which proved effective for
the prevention of more than one aging-related pathological process.
We feel that our success in introducing aging into the ICD is an
important step toward opening the doors to treating aging-related dis-
eases. However, the need to include aging per se as a unitary disease or
a separate classification of aging-related pathologies in the future ICD
frameworks is still present in order to facilitate the development of
clinical practice guidelines and therapies to alleviate health burden
associated with aging and aging-related diseases (Calimport, 2019).
5. Conclusions
This review shows that human aging can be described in terms of
the WHO criteria for disease, including symptomatology, aetiology,
course and outcomes of the disease, possible and potential interven-
tions, and linkage to genetic and environmental factors. Pathogenetic
processes of aging are highly interconnected (Fig. 1), and therefore,
aging can be defined as complex of several mutually-influencing pa-
thological processes.
The set of major pathogenetic processes of aging identified in this
study can be used for the development of clinically significant panels of
aging biomarkers targeting individual pathological processes.
Finally, we conclude that aging fits all of the six disease criteria
developed for the ICD-11 and can be considered a disease. The argu-
ment whether aging is a disease or a syndrome may look like a merely
semantic matter, however, considering aging a disease may accelerate
the development and implementation of innovative technologies to
prevent and cure aging-related pathologies.
Declaration of Competing Interest
There is no conflict of interest to declare.
Acknowledgments
We thank Ivan Alexeev, Edouard Debonneuil, John Furber, Aubrey
de Grey, Steven Hill, Boris Kaurov, Valentina Matveyeva, Aleksey
Moskalev, Valeria Pride, Paul Spiegel, Valeria Udalova, Alex
Zhavoronkov, Danila Medvedev, Arkadi Mazin and Viktor Zykov for the
assistance and advice.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.mad.2020.111230.
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