Heliyon 6 (2020) e04107

Contents lists available at ScienceDirect

Heliyon
journal homepage: www.cell.com/heliyon

Review article

Aging - Oxidative stress, antioxidants and computational modeling

Umm-e-Ammara Warraich a, Fatma Hussain a, *, Haroon Ur Rashid Kayani b
a
Department of Biochemistry, Faculty of Sciences, University of Agriculture, Faisalabad, Pakistan
b
Department of Software Engineering, Lahore Garrison University, Lahore, Pakistan

A R T I C L E I N F O A B S T R A C T

Keywords: Aging is a degenerative, biological, time-dependent, universally conserved process thus designed as one of the
Biological sciences highest known risk factors for morbidity and mortality. Every individual has its own aging mechanisms as both
Bioinformatics environmental conditions (75%) and genetics (25%) account for aging. Several theories have been proposed until
Biochemistry
now but not even a single theory solves this mystery. There are still some queries un-answered to the scientific
Pharmaceutical science
Reactive oxygen species
community regarding mechanisms behind aging. However, oxidative stress theory (OST) is considered one of the
Antioxidants famous theories that sees mitochondria as one of the leading organelles which largely contribute to the aging
Mitochondria process. Many reactive oxygen species (ROS) are produced endogenously and exogenously that are associated
Computer models with aging. But the mitochondrial ROS contribute largely to the aging process as mitochondrial dysfunction due to
oxidative stress is considered one of the contributors toward aging. Although ROS is known to damage cell
machinery, new evidence suggests their role in signal transduction to regulate biological and physiological
processes. Moreover, besides mitochondria, other important cell organelles such as peroxisome and endoplasmic
reticulum also produce ROS that contribute to aging. However, nature has provided humans with free radical
scavengers called antioxidants that protect from harmful effects of ROS. Future predictions regarding aging,
biochemical mechanisms involved, biomarkers internal and external factors can be easily done with machine
learning algorithms and other computational models. This review explains important aspects of aging, the
contribution of ROS producing organelles in aging, importance of antioxidants fighting against ROS, different
computational models developed to understand the complexities of the aging.

1. Introduction of age and above were present in 2010 (Chaves et al., 2017). By the year
2050, this number will become 1.5 billion (Lara, 2018). Throughout
Aging is a biological, degenerative process. It progresses slowly and is mankind history, aging that is a time-dependent functional decline has
much more complicated to be measured quantitatively. Aging results in provoked excited imagination and curiosity. Hence, to date, the most
functional decline of organisms such as physiological functions with time unanswered scientific question is the biological basis of aging
and hence chances of death and disease rate are increased (Lee and Wei, (L
opez-Otín et al., 2013; Jang et al., 2018).
2012; Labat-Robert and Robert, 2015; Kauppila et al., 2017). Even though among all organisms, aging is relatively a universally
The increased rate of life expectancy is a consequence of the avail- conserved process, but the basic molecular mechanisms remain widely
ability of treatments and better life quality conditions (Suzman et al., ambiguous (Cui et al., 2012). The activity theory that is an influential
2015). Numerous chronic and non-communicable diseases are respon- early theory reported the definition of successful aging as the mainte-
sible for disability and death worldwide (Szentesi et al., 2019). nance of attitudes and activities of younger and middle age as long as
The average life span for a healthy person is 80 years and aging leads possible (Nyberg and Pudas, 2019). Another study defines "successful
to mortality and pathophysiological conditions (Theurey and Pizzo, aging" as key ideas including longevity, satisfaction, mastery and growth,
2018). Muhammad ibn Yusuf al-Harawi in 1532 conducted the first less disability, independence and energetic life style (Martin et al., 2014).
documented study on aging in his book “Ainul Hayat”. Nearly 5 centuries Process of getting old is quasi-programmed, a continued program that
have passed, but the cause and mechanism behind aging are still nebu- is never turned off. A quasi-program can be defined as a developmental
lous (Peng et al., 2014). The challenging reality of this century is global program that continues purposelessly and after completion that would
aging. According to one study, about 576 million people having 65 years never switch off. And this is what the evolutionary theory predicts.

* Corresponding author.
E-mail address: [email protected] (F. Hussain).

https://doi.org/10.1016/j.heliyon.2020.e04107
Received 10 March 2020; Received in revised form 12 May 2020; Accepted 27 May 2020
2405-8440/© 2020 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
U.-e.-A. Warraich et al. Heliyon 6 (2020) e04107

Damage does not cause aging, in fact, aging causes damage, hence the speed of walking, unplanned loss in body weight, comparatively less grip
process of aging is not driven by damage (Blagosklonny, 2008). Human power, and problems in standing in an older person (Vi~ na, 2019).
body functions are deteriorated by aging, causing diseases and progres- Another study indicated that the free radical theory of aging must be
sive decline to resist stress (Davalli et al., 2016). modified with the argument that, though oxidants have adverse effects,
According to Biogerontologists, both genetics and environmental but they are also involved in signaling pathways and have a role in
conditions account for aging, that can be estimated by the fact that due to cellular senescence. Hence, according to this "Organisms age as accumu-
genetics 25% individuals get older while 75% individuals are accounted lated ROS dependent damage over time in cells” to “Organisms age as accu-
by environmental conditions, that include behavioral patterns (Fern
an- mulated damage and senescent characteristics, that are oxidants’-dependent,
dez-Ballesteros et al., 2013). Although some of the mechanisms and as- over time in cells” (Clement and Luo, 2019).
pects of aging involve gene-related processes, however aging is not Recently, a new concept termed "hormesis," has emerged. According
linked with genes (Labat-Robert and Robert, 2015). Thus, aging is a to this concept, the cell response can be improved by low doses of a
lengthy procedure attributed to personal and behavioral events and stressor for an extra damaging state. This may enhance cellular fitness
socio-environmental conditions, other than genes. Two factors determine and lifespan. Due to activation homeostatic responses, decreased ROS
the individual's capacity for aging well-healthy and active: behavioral levels may be advantageous, but damage or aging may occur due to its
selections and decisions taken (Fern
andez-Ballesteros et al., 2013; Lab- disproportional augmentation (Barbosa et al., 2018).
at-Robert and Robert, 2015).
2.1. Oxidative stress
2. Aging theories
Oxidative damage means the accumulation of free radicals due to free
Indeed, above 300 theories including many mechanistic and evolu- radical's over-production that cannot be processed gradually or because
tionary theories have been proposed by the scientific community to of less availability of antioxidants. It leads to a wide range of random and
explain why and how living organisms age and the driving force behind indiscriminate biomolecular damage (Simioni et al., 2018). Term
aging, but not even a single theory has been proved to be universally “oxidative stress” was first used in the 1970s & 1980s, for various dele-
applicative (Pomatto and Davies, 2018). For instance, according to the terious processes. However, it was later defined as antioxidants and ox-
"somatic mutation" theory, somatic mutation and increased DNA damage idants imbalance in favor of the oxidants, which potentially leads to
largely account for aging, while "telomere loss" theory suggests that with deterioration as shown in Figure 1 (Weidinger and Kozlov, 2015).
age cellular division capacity associated with progressive telomeres Oxidative stress occurs when the antioxidant buffering capacity is less
shortening in somatic tissues is decreased. However, the "altered proteins than the production of pro-oxidant compounds such as ROS (Czerska
and waste accumulation" theory postulates about association of certain et al., 2015; Pisoschi and Pop, 2015).
factors with some age-linked ailments, like protein turnover being The overabundance of ROS may initially enhance synthesis of
indispensable to conserve cellular function and accumulation of altered concomitant cytokine and promote inflammation, that can additionally
proteins and damaged proteins over time (Theurey and Pizzo, 2018). accelerate the ROS formation (Van De Lagemaat et al., 2019).
Hence, it is considered from all aging theories, from programmed cell Oxidative stress takes part in the development of aging and many
death to 'wear-and-tear', that ROS (reactive oxygen species) or free rad- degenerative and chronic disorders including autoimmune disorders,
icals account for age development. The message for research of aging inflammation, cancer, arthritis, neurodegenerative and cardiovascular
would read and summarized precisely and shrewdly as: It's the free diseases. Oxidative stress could actively provoke many abnormalities so
radicals” (Blagosklonny, 2008). it leads to initiate many ailments (Chandrasekaran et al., 2017; Simioni
Free radical theory of aging is extremely common concept based on et al., 2018).
work by Gerschman et al. (1954). They observed that oxygen toxicity is Various pathophysiological events could occur due to disruption in
caused by free oxygen radicals. It is assumed that "aging caused by free bio-signaling because of oxidative stress and subsequent alterations at
radicals that produce harmful side attacks on connective tissues and cell various levels of life, particularly in old age (Szentesi et al., 2019). The
components". However, free radical's production normally occurs during modulation of ROS location, inactivation and production occur contin-
cellular metabolism. Therefore, the idea sparked from Harman's theory uously in both pathological and physiological conditions, if a fine balance
that cellular damage could be mitigated by the complete removal of is maintained between oxidant-antioxidant mechanisms (Davalli et al.,
so-called harmful molecules, as a consequence, slowing the overall pro- 2016).
cess of aging (Pomatto and Davies, 2018). Unfortunately, skin is the only
organ in human body where this theory seems true. The comparison 2.1.1. Production of ROS
among different organs regarding ROS load indicates that skin contains a During the cellular redox process, byproducts are generally produced
higher ROS load as compared to other organs, also in many cases, a clear such as RONS (reactive nitrogen species) as well as ROS (Pham-Huy
correlation can be found between a pro-aging effect and the origin of ROS et al., 2008). These products define the radical and non-radical active
from internal and external insults. The fact that distinguished this organ compounds of nitrogen and oxygen (Powers et al., 2011).
is that like intrinsic aging, extrinsic aging is also, important (Rinnerthaler The exogenous ROS and RONS sources that metabolized as free rad-
et al., 2015). Environmental influences such as ultraviolet (UV) radiation icals include water and air pollution, drugs, alcohol, tobacco, heavy or
exposure that contributes up to 80% to skin aging defines extrinsic type transition metals, radiation and cooking products. The endogenous RONS
whereas the corporal changes and genetic factors elaborate the intrinsic sources are lipoxygenase, myeloperoxidase (MPO), angiotensin II and
aging that happens during normal aging process (Farage et al., 2008; nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The
Ferri et al., 2019). major sources of ROS within cell are enzymes (Liguori et al., 2018).
According report stated that free radical theory is not applicable and There are multiple enzymes and multiple compartments within the
hence this theory was dismissed in 2014. The argument that support this cell where ROS are generated. This includes compartments such as
statement is the participation of ROS to the aging process occurs by the cytoplasm, oxidase and cyclooxygenases, NADPH oxidase at plasma
assist of cell's metabolic organization, individual's genotype and protec- membrane, mitochondria during oxidative phosphorylation and lipid
tive systems. Hence, as by-products, ROS cause cellular damage (Carocho oxidation within peroxisomes. Though the overall oxidative burden
et al., 2019). So, a new theory “a free radical theory of frailty” was comes from these sources in aging, maximum ROS production occurs
defined that damage due to oxidation associates with both sequential during oxidative phosphorylation (Dai et al., 2012; Flores-L

opez., 2019).
aging and frailty. Frailty is a geriatric perception in which there is the Apart from these sources, other major sources of endogenous oxidants
appearance of certain factors such as lack of feeling wellbeing, lesser include cytochrome p450, nitric oxide synthase, monoamine oxidase,

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U.-e.-A. Warraich et al. Heliyon 6 (2020) e04107

Figure 1. Free radicals and antioxidants imbalance causes oxidative stress and results in aging, while several endogenous and exogenous ROS sources contribute to
aging (Weidinger and Kozlov, 2015).

many oxidoreductases including xanthine oxidase, mitochondrial respi- Different types of ROS have distinct properties. Highly reactive oxy-
ratory chain (RC) and enzymes responsible for infection and inflamma- gen species (hiROS) are harmful for biomolecules. Less reactive oxygen
tory responses to stimulate xenobiotic such as NADPH oxidases (Haeri species (loROS) take part in cellular signaling include superoxide and
and Knox, 2012). The observations show that oxidants production from especially hydrogen peroxide (Scialo et al., 2013). The family of highly
these sources has ability to rise with age and varies with pathophysio- reactive molecules is called ROS physioma, these are free oxygen radicals
logical conditions (Zhang et al., 2015a,b). However, endogenous oxi- (hydroxyl radical; HO⋅, superoxide anion; O⁻₂) and non-radical oxygen
dants produce during the lifetime, a continuous process, so contact with derivatives (hydrogen peroxide; H2O2). Other ROS formed from super-
internal oxidants sources is much more extensive (Simioni et al., 2018). oxide radicals such as hydroxyl radicals, hydrogen peroxides which
Compounds (radicals, non-radicals) with oxygen are potent and able interconvert with reactive nitrogen species (RNS), have similar effects as
to initiate some kind of detrimental reaction, indicated as ROS. These that of ROS (Davalli et al., 2016).
include hydrogen peroxide (H2O2), superoxide anion (O⁻), hypochlorous Various cellular activities are accomplished by ROS such as cell
acid (HOCl), peroxyl radical (HO2), alkoxyl radical (RO⋅), hydroperoxyl, signaling transduction, gene transcription, immune response, cell death,
singlet oxygen (O2) and hydroxyl radical (HO⋅) (Lambert and Brand, cell survival, differentiation, and inflammation. An equilibrium between
2009; Cui et al., 2012). ROS include oxygen derivative and are oxidizing oxidation species and antioxidants (AOs) is significant for biological role,
agents either radical or non-radical and/or that are converted into rad- growth, adaptation and regulation ((Lushchak, 2015; Weidinger and
icals easily (Genova and Lenaz, 2015). Kozlov, 2015; Liu et al., 2018; Flores-L
opez et al., 2019).
The free radicals are produced when cells need to generate energy by
using oxygen, so the ATP production by mitochondria results in free 2.2. Mitochondria and aging
radicals production (Pham-Huy et al., 2008). They are also produced
during different aerobic processes such as during intensive physical ac- Human mitochondrial DNA (mtDNA) consists of 16, 659 base pairs.
tivity, cellular respiration and microbial infection exposure that involves There are many mtDNA copies in the mitochondria of mammalian cells.
phagocyte activation (Pisoschi and Pop, 2015). Free radicals were There are 13 proteins, tRNA and rRNA coded by human mtDNA and they
identified in biological systems in the 1950th, after their existence, it was are indispensable for the structural and functional preservation of
supposed immediately that they are involved in aging and other diverse mitochondria (Dr€ ose and Brandt, 2012). Numerous studies proposed that
pathological processes (Lushchak, 2015). ATP production can be influenced by mutations in mtDNA. Several ail-
When certain molecules interact with oxygen, free radicals with one ments such as early aging process and neurodegeneration are linked with
or more unpaired electrons in their outermost shell are produced. These disturbances in mtDNA integrity (Kawamura et al., 2018). Different key
active free radicals behave as oxidants or reductants as they are produced metabolic pathways take place in mitochondria including fatty acid
by losing or accepting a single electron in cells (Liguori et al., 2018). β-oxidation, one-carbon cycle and tri-carboxylic acid (TCA) cycle (Mail-
Free radicals may have zero, negative or positive charge. The specie loux, 2015; Zhang et al., 2018). It is responsible for the production of
that has two unpaired electrons is a radical such as diatomic oxygen O2. cell's 90% energy (Marchi et al., 2012). Disturbances in mitochondrial
While both the electrons have a similar spin quantum number but the function is assumed as a symbol of aging (Bolduc et al., 2019).
location of each electron is in the different π* anti-bonding orbital. Thus The mitochondrial ROS production and damage to DNA occurs with
their low reactivity with non-radical molecules is attributed to this par- the passage of time and eventually results in inability of cell to identify
allel spin. Though, O2 can be converted in to much more reactive singlet the key role of mitochondria. This fact led to formulate “mitochondrial
oxygen O2, by providing an energy input that can invert spin of one of the free radical theory of aging” (MFRTA), though it is quite controversial
unpaired electrons. Hence both the electrons may either form a pair in (Son and Lee, 2019). It was modified, expanded and challenged by many
the similar π* orbital or may remain in two different orbitals. The elec- researchers but two fundamental statements were never changed. Firstly,
tron addition to an oxygen one at a time can overcome the spin restric- oxidatively damaged macromolecules accumulation with aging due to
tion. During normal aerobic metabolism, non-radicals are produced in antioxidant/oxidant imbalance, Secondly, degenerative aging phenotype
the body such as H2O2, they are also synthesized in the body during stress due to accumulated oxidative damage. First point is well accepted that an
conditions (Genova and Lenaz, 2015). imbalance of oxidant/antioxidant in the elderly results in the

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accumulation of damaged molecules due to oxidative damage while has its own distinct properties and is associated with RC and substrate
some studies challenged the second point (Zhang et al., 2015a,b). catabolism (Brand, 2016).
Currently, MFRTA is well-known theory (Lara, 2018), now termed An electrochemical gradient is generated when electrons are
Oxidative Stress Theory (OST). sequentially transported from CI or CII to CIII and complex IV. Ultimately
Several studies proposed alterations in mtDNA and mitochondria, transport of protons into inter-membrane part from matrix occurs. During
decreased oxidative phosphorylation, increased structural disintegration, this transmission, hydrogen peroxide (pair-electron transfer) or super-
elevated ROS synthesis and hazardous effects on fats, proteins and oxide (single-electron transfer) are produced by the direct transfer of
nucleic acids during aging. Estimated mutation rate of mtDNA is 10 times electrons to oxygen, principally at complex I, II and III, having acceptor as
more than DNA present in nucleus with lesser ability of repairing, lack of ubiquinone (Eleutherio et al., 2018).
histones, such aspects influence aging and cancer (Kammeyer and Luiten, Surprisingly, production of ROS by RC complex IV (cytochrome c
2015; Haas, 2019). oxidase) does not occur, though it reduces oxygen to water, demon-
As the above discussion demonstrates that the main site of ROS strating that in RC, production of ROS and leakage of electron can be
synthesis is mitochondria in mammals, thus the mtDNA are more prone prevented. Production of ROS by CI and CIII are important in regulating
to harm because of their presence adjacent to site of ROS production. various pathological and physiological processes that range from cellular
Consistently, it has been indicated by many studies that mtDNA contains differentiation to damage during reperfusion/ischemia (Reczek and
a elevated concentrations of 8-hydroxy-20 -deoxyguanosine 8-oxo-dG as Chandel, 2015; Scial o et al., 2017), while the development of certain
compared to nuclear DNA, 8-oxo-dG is byproduct of oxidation (Cui et al., types of cancer is mediated by the production of ROS from CII. ROS
2012). produced by CIII are divided among matrix and inter-membrane part.
Decline in mitochondrial activity is linked with onset of many dis- ROS formed by CI are send to matrix. This demonstrates that both
eases (Sun et al., 2016). However, general concept is that the accumu- complexes follow diverse distribution systems (Stefanatos and Sanz,
lation of random molecular damage due to ROS largely contributes to 2018).
aging (Blagosklonny, 2008). During aging, damaged mitochondria in- During electrons transport from NADH to CoQ in CI, ROS can be
crease in number and these synthesize greater amount of ROS and less created at both sites, site IQ (CoQ binding site) and site IF (FMN site) in
ATP (Stefanatos and Sanz, 2018). The adverse effects due to damaged the matrix. ROS production in CII occurs at the IIF site, which is linked
DNA occurs in cells by transcription, blocking replication, chromosome with succinate dehydrogenase. Only small amounts of ROS are produced
rearrangements, generation of breaks in one or both strands of DNA by CIII which are negligible compared to ROS production of CI. ROS
(Fakouri et al., 2019). produced by CIII are transferred to matrix and into intermembrane space
However, these phenomenon of somatic mtDNA mutations and DNA (IMS). The ROS released into the IMS undergo a reaction catalyzed by
strand breaks may be induced by progressive oxidation reactions with superoxide dismutase (SOD) i.e., SOD2 in matrix and SOD1 in IMS).
increase in age. Impairment of RC complexes occurs by the accumulated There it is converted into H2O2 which has important role in pathophys-
mtDNA alterations, results in a vicious cycle with the more mitochondrial iological pathways. Superoxide is short-lived, presumably acts where it is
DNA mutations and elevated ROS synthesis (Bonomini et al., 2015). produced, and poor membrane-permeability compared to H2O2 that is
Thus, current consensus indicates that damaging mitochondria, oxidative more stable, uncharged and permeable through aquaporin channels
stress and ultimately an energetic crisis by ROS accelerates aging and hence more versatile signaling molecule. However, similar to superoxide
triggers neurodegenerative diseases (Stefanatos and Sanz, 2018). mtDNA species, H2O2 produces significant oxidative damage to biomolecules in
damage is associated with aging, but it is unclear whether mitochondrial the presence of free Fe2þ. Formation of extremely active OH-radicals
dysfunction or mtDNA damage is directly involved in vascular aging occurs when this cation is present as shown in Figure 2 (Wang et al.,
(Foote et al., 2018). 2018; Zsurka et al., 2018; Zhao et al., 2019).
There are at least nine mitochondrial sites where the generation of
2.3. Mitochondrial ROS superoxide anion takes place, a progenitor ROS (Andreyev et al., 2005).
Furthermore, superoxide is also produced by a family of
ROS synthesis in RC was first reported in 1966, which came from the membrane-bound enzymes called NADPH oxidases, that by coupling
pioneering work of Chance and colleagues (Chance et al., 1979). NADPH-derived electrons to oxygen, catalyze controlled O2 production
Major sources of ROS production are first and third complex of RC, (Labunskyy and Gladyshev, 2013).
where free radicals are generated when oxygen or other electron ac- The significance of appreciating the topology of ROS production sites
ceptors react directly with electrons derived from ubiquinone and NADH. and finding the difference between different ROS especially hydrogen
Thus the normal side products of the respiration process are ROS that peroxide and superoxide is evident: oxidation-reduction bio-signaling
react with protein, fats and nucleic acid, hence damage these bio- generated by superoxide by site IQ in matrix may vary from such bio-
molecules (Marchi et al., 2012). signaling send by superoxide into cytosol by complex IIIQo, addition-
The significant production of ROS occurs by isolated mitochondria ally, redox signaling by hydrogen peroxide will be different from both
via two modes of operation, chiefly from (i) first complex when coen- these, formed on any side of the inner mitochondrial, indirectly or
zyme Q is reduced and has large proton motive force (Fp) due to zero directly (Brand, 2016).
production of ATP from mitochondria; (ii) when mitochondrial matrix The partial reduction of approximately 1–5% of the total oxygen that
contains a higher reduced to oxidized ratio of NAD. The amount of O2  is consumed by mitochondria results in ROS production that is the for-
produced is less when ATP production by mitochondria occurs actively, mation of superoxide anion radical (O2). One study revealed that 1%–
and as a consequence have a lower NADH/NADþ and Fp ratio (Murphy, 3% of oxygen is converted into free radicals during normal physiologic
2008). conditions when consumed by the body, but free radicals production
In isolated mitochondria, ROS can be produced in up to eleven increases promptly beyond metabolically required amounts when
distinct sites. However, it has been shown that in vivo ROS production oxidative stress occurs (Brawek et al., 2010; Buehler, 2012).
takes place only at three sites that are more relevant: respiratory complex Mitochondrial membrane potential (ΔΨm), activity RC complexes
CIII (aka Ubiquinol: cytochrome c reductase, complex II (CII aka succi- and ROS production rate are strongly related. Hence, if respiration is
nate dehydrogenase) and complex I (CI aka NADH: ubiquinone oxido- inhibited and increased ROS production results by the mitochondrial
reductase) (Stefanatos and Sanz, 2018). Recently it has been investigated membrane potential dissipation then a reduced rate of free radical gen-
that appreciable O2– formation occurs at complex II (Robb et al., 2013). eration occurs if uncoupling stimulates drop in ΔΨm. Despite the fact
It is now known that from at least 11 different sites, mammalian mito- that major ROS generation takes place in RC under the resting situation,
chondria can produce hydrogen peroxide and/or superoxide. Each site generation of (O2) could also occur by various complexes and matrix

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Figure 2. Generation of ROS in the electron transport chain through complex I, II, III and the formation of OH-radicals in the presence of free Fe2þcation by Fen-
ton reaction.

proteins such as enzymes (α-ketoglutarate dehydrogenase, pyruvate de- signal transduction to regulate biological and physiological processes
hydrogenase, aconitase) Krebs cycle (Angelova and Abramov, 2018). (Cheng and Ristow, 2013). Oxidative stress leads to pathophysiology and
Researches demonstrated that during the aging, RC function is aging. To minimize these deleterious effects, antioxidants are prescribed.
compromised which might be due to a high level of accumulated ROS However, it is clinically proven that this may not be as efficient as ex-
from altered metabolic process and weakened antioxidant defense. pected. Such supplementations failed to improve health. It is suggested
However, the induction of mitohormesis to prevent age-related diseases that some molecular aspects of cellular respiration such as ROS are not
at young age and manipulation of RC activity to prolong lifespan in late- harmful. ROS exerts positive effects on health during stressful situations,
life through pharmaceutics will be a promising avenue to pursue (Bouska although its mediation and regulation mechanisms are not known (Ris-
et al., 2019). tow, 2014).
One study indicated that degenerative cellular features of Friedreich's By limiting glucose and calorie intake, cells provoke mitochondrial
ataxia (FRDA) may appear due to mitochondrial ROS production which is metabolism that leads to longevity. Contrary to the findings depicted in
enhanced by the frataxin deficiency in mitochondria. The study sug- Harman's theory of aging, these effects may be attributed to the elevated
gested that complex IV defect is produced by defective heme synthesis production of ROS that induces resistance against stress. Actively
and defective expression of heme and cytochrome c in Complex III and IV respiring mitochondria produce ROS that promotes long life. ROS act as
results in increased ROS in FRDA cells. Thus, in FRDA, heme defect biosignaling molecules that initiate internal defense processes that lead
causes increased mitochondrial ROS and limited cytochrome c and oxi- to enhanced stress resistance. This type of adaptive reaction is known as
dase action, all due to defects in Fe–S centers (ISC). This leads to shortage named mitochondrial hormesis (mitohormesis). This phenomenon offers
of heme and ultimately more ROS production, so it is not surprising that a mutual mechanism denominator for bioactive roles of exercise,
defects in mitochondrial pathway for heme happens with increasing age restricted calorie, and glucose intake (Ristow and Schmeisser, 2011;
(Napoli et al., 2006). Ristow and Zarse, 2010).
Recent data indicate that in deteriorating diseases related with aging, Survival in saturated oxygen atmosphere demands efficacious phys-
the activation of mitochondrial permeability transition pore (mPTP) (an iological approaches to identify and eliminate metabolic by-products; the
inner membrane protein complex that can form voltage-gated nonse- oxidants. Oxidative tensions are linked with ageing and longevity (Finkel
lective channel) is triggered by ROS and when mitochondria are over- and Holbrook, 2000). Though the behavior of oxidants is haphazard and
loaded with calcium. The full opening of the mPTP initiates not only damaging, their generation is securely controlled in several cellular
further release and production of ROS that may not only harm DNA, events. These oxidants are effector molecules for myriad pathways
phospholipids and proteins but also cause release of matrix DNA to (Finkel, 2003). Aging and related diseases might have common under-
intermembrane space where it is hydrolyzed. This causes depletion of lying physiological mechanisms as with an increase in age susceptibility
cellular DNA that contributes in accelerating the aging process. It is to develop numerous diseases also rises. ROS generated during oxidative
assumed that aging increases mPTP opening and vice versa. ROS also phosphorylation may affect the rate of aging and exposure to disease
triggers the activation of mPTP. This can further aggravate clinical fea- (Finkel, 2005).
tures of FRDA as mitochondria itself get damage during oxidative re- Under mild stress conditions, mitochondria stimulate signaling
actions because of activated mPTP. The majority of the ROS and pathways in cytosol that affect gene expression, making the cell less
'mitochondrial dysfunction' effects on lifespan and aging are mediated vulnerable to expected perturbations. Such a response known as mito-
through the mPTP activation (Rottenberg and Hoek, 2017; Panel et al., hormesis has been extensively studied. Comprehensive knowledge of
2018). mitohormesis will highlight the unanimous theory of aging (Yun and
Finkel, 2014).
2.3.1. ROS-induced health benefits It has been observed by Ristow and Schmeisser (2014) that super-
Homeostasis of metabolism relies on the functionality of mitochon- oxide, hydrogen peroxide, and other ROS may act as signals to prevent or
dria. Mitochondria not only convert the chemical energy of reduced delay numerous diseases and thus increase longevity. Low concentrations
organic compounds into energy currency of the cell; the ATP but also of ROS ameliorate physiological defense systems by initiating adaptable
produce numerous biosynthetic intermediates and ROS. ROS damage strategies. ROS mediated signaling actions include downstream of
lipids, proteins, and DNA. However, it is suggested ROS also play a role in insulin/IGF-1 receptor, AMP-dependent kinase (AMPK),

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generation of inflammatory responses are subjected to redox regulation.

Table 1. Types of antioxidants. Impaired ROS signaling can lead to numerous diseases (Finkel, 1998,
Endogenous Antioxidants Exogenous Antioxidants 2011).
Enzymatic Mineral elements Limited data exist regarding redox reactions regulations in non-
Catalase Selenium phagocytic cells, particularly the origin of oxidant generation, and
Superoxide dismutase Zinc their targets within the cell. Active alterations in the redox environment
Glutathione Manganese act as determining factors in cell choices for growth, programmed cell
Glutamyl trans peptidase Copper
Non-Enzymatic Nutritional
death and (Finkel, 1999).
Uric acid Carotenoids According to West et al. (2011a), innate immune systems are sup-
Ubiquinone Vitamin C ported by mitochondria. In mouse macrophage, bactericidal activity is
Tocopherol Vitamin E mediated by mitochondrial ROS (mROS). However, the mechanism that
Retinol Phytochemicals
links inborn immune signals to mROS generation is still not clear. TLR1,
Glutathione Supplementations
Melatonin β-carotene, coenzyme Q10 TLR2, and TLR4 are Toll-like receptors that are used to involve mito-
Nuclear factor erythroid Lipoic acid, Glutathione chondria for ROS synthesis. The biochemical mechanism of elevated ROS
2-related factor 2 (NRF2) Phytoestrogens, Polyphenol synthesis involves TLR signaling adaptor, TRAF6 (tumour necrosis factor
receptor-associated factor 6), evolutionarily conserved signaling protein
Toll pathways (ECSIT). Additionally, mitochondria regulate antiviral
target-of-rapamycin (TOR), and sirtuins to end regulation of proteostasis,
signaling (West et al., 2011b).
unfolded protein response (UPR), stem cell maintenance and stress
It is stated by Schroeder et al. (2013) that extension in life span
resistance.
emerges from adaptive signaling mechanisms influenced by slightly
Living organisms can produce energy, transform it, and consume
higher ROS levels. Stress-induced signals exist between mitochondria
organic compounds for growth and reproduction. During bioenergetic,
and nucleus and these are involved in the regulation of aging through
oxidative phosphorylation in eukaryotic cells produce ATP and ROS.
epigenetic silencing of gene expression, thereby initiate longevity effect.
Although ROS is known to damage cell machinery, new evidence sug-
Further studies are warranted to determine the nature of reactive
gests their role in biosignaling (Shadel and Horvath, 2015). Lu and Finkel
chemical species that are involved in signal transduction, ligand stimu-
(2008) reviewed different studies where entrance into cellular senes-
lation, and protein targeting. The mechanisms by which these oxidants
cence had been assessed when ROS concentrations were moderated by
transduce signals should be explored to enhance our understanding
growth in elevated or reduced oxygen level environment or when the
about different pathophysiological states (Finkel, 2000, 2012).
antioxidant status was disturbed. It was also observed that senescence
caused by oncogene expression is partially facilitated by ROS levels.
2.3.2. Mitochondrial homeostasis and mitophagy
However, it is not known whether ROS acts randomly or specifically and
Recognition of gene variants responsible for longevity elaborated
which specific chemical specie is the actual triggering molecule.
aging biology. Research in the field of aging has social, therapeutic, and
Multiple downstream signaling actions require ROS. When ligand-
marketable values (Campisi et al., 2019). Numerous biochemical phe-
triggered ROS generation was characterized, it revealed valuable
nomena such as bioenergetics, genomic stability, mitochondrial ho-
insight into oxidases composition and GTPases-dependent regulation
meostasis, cellular adjustments under stress, and cell existence have
(Finkel, 2001).
involvement of NADþ, an essential metabolic molecule. Several enzymes
Similarly, Holmstro €m and Finkel (2014) stated that redox-dependent
involved in brain activity depend upon NADþ. NADþ and other associ-
bio-signaling encompasses oxidation reduction reactions at cysteine
ated metabolites play a crucial role in neuron's adaptive strategies against
amino acid mostly. For this purpose, the generation of oxidants is ensured
stress inducers and corrective counteractions in progressive brain dete-
due to their role in self-renewal of stem cells, tumorigenesis, immune
riorating conditions (Lautrup et al., 2019). NADþ depletion is a vital
response, and aging. Some features of the aging process such as senes-
characteristic of aging and it can lead to many chronic diseases. Reduc-
cence, inflammation, and the loss of stem cell activity are provoked by
tion in NADþ concentration is observed not only in neurodegenerative
mitochondria. Signaling pathways regulate mitophagy and longevity
diseases but also in aging. Physiological and therapeutic interferences
(Sun et al., 2016).
that boost NADþ levels may delay aging and associated diseases (Fang
ROS regulates signaling within the cell by covalent alterations of
et al., 2017).
cysteine residues of specific proteins. Such oxidative modifications can
NM signaling (signaling from the nucleus to mitochondria) regulates
amend enzyme activity. Response to growth factor stimulus and
mitochondrial function and ageing. Nuclear DNA damage is the starter of

Figure 3. Standardized data sets of blood biochemistry for laboratory analysis, diverse deep neural network with different characteristics pooled collectively in
ElasticNet model (Putin et al., 2016).

6
U.-e.-A. Warraich et al. Heliyon 6 (2020) e04107

this signaling, and this DNA accumulates with age. NM signaling system hydrogen peroxide sensors (Kritsiligkou et al., 2018). Both glutathione
has sirtuins proteins, that ensure DNA and mitochondrial stability (Fang peroxidase and peroxiredoxins, ER-localized enzymes, scavenge
et al., 2016). Nicotinamide adenine dinucleotide (NADþ)-dependent hydrogen peroxide to water by donating electrons from PDI to hydrogen
deacylases, sirtuins (SIRT1-7) have extraordinary capabilities to avert peroxide (Siegenthaler and Sevier, 2019).
diseases and ageing effects. Animal models had better organ physiology,
physical strength, disease defiance, and long life when treated to express
extra sirtuins (SIRT1 or SIRT6), or given STACS (sirtuin-activators) like 2.5. Antioxidants
resveratrol and SRT2104 or with NADþ precursors. It was concluded that
STAC can be used to treat inflammatory and metabolic diseases (Bon- ROS have a role in carrying out the vital physiological processes.
kowski and Sinclair, 2016). Although elevated ROS levels lead to stress and pathology, reduced ROS
levels are associated with the normal physiological conditions (Banerjee
2.4. Other organelles and aging et al., 2017; Bodega et al., 2019).
Presence of free radicals near tissues and cells induces a series of
Many organelles are involved in generation of significant amounts of reactions and activates certain multiple internal defense cellular pro-
ROS. Cellular ROS concentrations depend upon mechanisms of ROS cesses to eliminate ROS (Miro
nczuk-Chodakowska et al., 2018). The cells
generation and this would ultimately result in initiating redox strain and and the organism have a specific anti-oxidative protection system to
signaling. Most important organelle is peroxisome that is involved in defend themselves (H€ ohn et al., 2017).
detoxifying and generating hydrogen peroxide. Accordingly, within The oxidation of substrate is prevented by antioxidants that are pre-
peroxisomes loss of redox homeostasis correlates with the induction of sent in smaller amounts in body and hence have a principal role in the
cellular senescence and increased hydrogen peroxide levels. Lysosomes defense mechanism (Suleman et al., 2019). Antioxidants quench or
contribute to the turnover of damaged organelles and proteins (Stefa- inhibit the reactions caused by free radicals and ultimately prevent or
natos and Sanz, 2018). delay cellular damage. The existence of the anti-oxidant defense mech-
The word “peroxisome” was originally derived for any cell organelle anism is universal, although there are variations in antioxidant defenses
which possesses at-least one H2O2-detoxifying enzymes either catalase or between different species (Nimse and Pal, 2015).
H2O2-producing oxidase (Titorenko and Terlecky, 2011). Peroxisomes In humans, three lines of defense have been evolved by nature. They
play a primary role in lipid metabolism. It is suggested that peroxisomes function through different mechanisms as; Inhibiting, Catching and
may perform a physiological function in aging. Moreover, it has been Restoring. The first line of defense that scavenges ROS/RNS involves
demonstrated that mitochondrial redox balance can be influenced by enzymatic and non-enzymatic antioxidants. They can delay or prevent
changes in the peroxisomal ROS metabolism (Fransen et al., 2012). initiation of different oxidative stresses directly and these include
Consequently, accelerated aging and stress may be due to loss functional glutathione (GSH), uric acid, vitamin E and vitamin C. The non-
ability of both organelles. Through specific protein complexes, peroxi- enzymatic substances in blood plasma such as transferrin, ferritin,
somes can physically connect with mitochondria. Hence, the functional ceruloplasmin and albumin belong to preventive antioxidants and they
and structural association of organelles are vital and active sign to inhibit new reactive species formation by binding transition metal ions
regulate aerobic metabolism, but real chemistry will be exposed in up- (e.g. copper and iron). Another defense line consists of non-enzymatic
coming days (Pascual-Ahuir et al., 2017). However, very limited antioxidants that serve as an intermediate defense to inactivate oxi-
knowledge exist regarding the involvement of peroxisomal ROS (H2O2, dants and radicals. The third and last line of defense involves repairing
NO) in bio-signaling that has fundamental involvement in the patho- and damage-removing, causing regeneration of damaged bio-molecules
genesis of aging and carcinogenesis (Antonenkov et al., 2010). from oxidative injury (Lei et al., 2015; Miron
czuk-Chodakowska et al.,
Peroxisomes by keeping many scavenging enzymes catalase and 2018; Neha et al., 2019).
peroxiredoxins as well as ROS-producing oxidases, not only regulate the Anti-oxidants terminate oxidative chain reactions by binding with
intra peroxisomal ROS homeostasis but can also help in the regulation of free radicals and donate their electrons to them, hence making free
extra peroxisomal ROS levels within the whole cell (Titorenko and Ter- radicals unavailable for further attack. After donating their electrons, the
lecky, 2011). free radical state is attained by antioxidants. Hence they are not harmful
For metabolically active tissues such as liver, peroxisomes are not because they have the ability to accommodate the change in electrons,
only the sources of ROS production and oxygen utilization (up to 35%). without themselves being reactive (Ahmad, 2018).
Peroxisomes, the highly oxidative organelles possess multiple antioxi-
dant systems, which are vital for its ROS homeostasis (Pascual-Ahuir 2.5.1. Endogenous antioxidants
et al., 2017). Endoplasmic reticulum (ER) oxidative folding machinery Antioxidant can be divided into enzymatic and nonenzymatic ROS
generates H2O2 during protein folding and incorporates ER scavengers on the bases of their biological function. The main enzymatic
oxidation-reduction, ER forms contact sites with mitochondria that are antioxidants are catalase (CAT), superoxide dismutase (SOD), gluta-
known as mitochondria-associated membranes (MAMs) (Rieusset, 2018; thione peroxidase, glutathione reductase, glutamyl Transpeptidase (GT).
Siegenthaler and Sevier, 2019). Non-enzymatic antioxidants are dietary compounds including minerals
It is experimentally estimated that during oxidative protein folding in (selenium, zinc) vitamins (C, E) and also uric acid, ubiquinol, tocopherol,
ER, about 25% of ROS are produced by disulfide bonds. Hence, more ROS retinol and glutathione (Momtaz and Abdollahi, 2012). Both
are generated from proteins having more disulfide bonds in comparison non-enzymatic and enzymatic antioxidants function in different cellular
with the proteins having fewer such bonds (Zeeshan et al., 2016). Two ER compartments and against different oxidative species, hence they are
enzymes ER oxidoreductin 1 (ERO1) and protein disulfide isomerase complementary to each other. Additionally, they perform their functions
(PDI) are considered to be an electron transport chain that is similar to with exogenous antioxidant systems in a synergistic way (Petruk et al.,
mitochondrial RC because in a nascent secretory protein during forma- 2018). Many fresh and raw foods contain minerals or essential vitamins.
tion of a disulfide bond, electrons are lost and are transferred to these Collectively, these nature-derived molecules are known as "phytonu-
enzymes. Hence, results in the formation of hydrogen peroxide as elec- trients" (Bjørklund and Chirumbolo, 2017).
trons are eventually transmitted from ERO1 to molecular oxygen (Sie- Researches have shown that nuclear factor (erythroid-derived 2)-like
genthaler and Sevier, 2019). 2 (NRF2), fight contrary to stress by transcriptionally up-regulating the
ER also contains different systems to restrict the accumulation of ROS, genes. NRF2 loss causes unlimited oxidative stress and drive the aging
likewise mitochondria. For example, ER contains peroxiredoxins that phenotype. Most endogenous antioxidants are expressed only when
play important roles in redox signaling such as thiol oxidizers and both NRF2 is activated (Aguilar et al., 2016; Schmidlin et al., 2019).

7
U.-e.-A. Warraich et al. Heliyon 6 (2020) e04107

Melatonin together with its metabolites has long been recognized in group of molecules. The chemical properties and physical location
protecting the cells exposed to toxins or in alleviating the burden of (emulsion interfaces, proximity to membrane phospholipids or in the
oxidative stress in aging cells. One study reported that melatonin is"al- aqueous phase) determine the anti-oxidative effectiveness of these
ways present at the right place within cell" to fight against stress. compounds (Oroian and Escriche, 2015).
Recently, it has been demonstrated that high concentration of melatonin Antioxidant supplementation catalyzes the degradation of organic
are available when abundant free radicals are present (Reiter et al., peroxides and hydrogen peroxide, superoxide and detoxifies oxy radicals
2018). and finally their conversion into the water, oxygen, and alcohol (Santos
et al., 2018). Many antioxidants such as superoxide dismutases, perox-
2.5.2. Exogenous anti-oxidants iredoxins, catalases, and reduced glutathione are made by humans
Human body lacks non-enzymatic anti-oxidants and hardly produces themselves. However, in recent years the discovery of per-oxiredoxins is
them, hence there are exogenous antioxidants. There are three categories one of the biggest advances. Peroxiredoxins have many fascinating
of exogenous non-enzymatic antioxidants: i) mineral elements such as properties, most importantly their ability to act as scavengers of H2O2 in
selenium ii) nutritional antioxidants like carotenoids, vitamin E and vivo (Halliwell, 2012).
vitamin C and iii) natural antioxidants: obtained from natural resources Another study reported the production of different specific
commonly known as phytochemicals/phytonutrients (Santos et al., mitochondria-targeted antioxidants (such as anti-oxidants conjugated
2018). All the antioxidants are known as Total Antioxidant Capacity with mitophenyltertbutyline and triphenylphosphonium cation e.g.,
(TAC) that reflects a general status of antioxidants (Momtaz and Abdol- mitovitamin E, mitophenyltertbutyline and mitoquinone). However, they
lahi, 2012). Nutritional antioxidants are primarily free radical scavengers are under experimental testing and development, and still, their role in
but they function in different compartments with different mechanisms. inhibiting vascular inflammation and mitigating the effects of oxidative
They act as free radical scavengers by 1) decreasing the production of stress in aging has not been evaluated (Ungvari et al., 2010).
ROS, 2) repairing the oxidized membranes, 3) neutralizing the free Another observation has shown the role of p53 in enhancing the
radicals, 4) through lipid metabolism in which cholesteryl esters and antioxidant gene expression, which accounts for the ability of p53's in
short-chain free fatty acids neutralize ROS (Simioni et al., 2018). regulating the oxidative stress in mice and cells (Vigneron and Vousden,
Though genetic aspects have a great impact on longevity, the envi- 2010). Different studies have indicated that dried fruits such as dates and
ronmental factors are also important, however, among them, the diet has peaches contain a higher concentration of corresponding antioxidant
the most influence on longevity (Aversa et al., 2016). A study was con- activities and bioactive compounds as compared to their respective fresh
ducted in healthy subjects aged 65–94 to evaluate the antioxidant status counterparts. The reason why dried fruits are rich sources of antioxidant
which showed the higher concentration of antioxidant in healthy cen- polyphenols is that after the process of dehydration antioxidants become
tenarians, indicating the great importance of diet rich in antioxidants and concentrated (Chang et al., 2016).
ultimately healthy centenarians have a lower degree of oxidative stress as Recently, researchers focused more on replacing synthetic antioxi-
compared to aged subjects. After eradication of statistically confounding dants with efficacious natural antioxidants (Li et al., 2013). Presently,
factors, their vocabulary and memory are tested which showed circu- polysaccharides have been extensively utilized and are obtained from
lating levels of beta-carotene and vitamin C, both these antioxidants species of Hericium, Lentinula, Ganoderma, Tremella, Pachyme (Zhang
appeared as predictors of their best efficiency (Mecocci et al., 2018). et al., 2017). Another study reported the effectiveness of taxanthin (3,3
Furthermore, the importance of diet rich in antioxidants can be P-dihydroxyl-4,4P-dioxo-L-carotene) as an anti-oxidant agent. Taxanthin
determined by the conditions in which endogenous antioxidant systems a common lipophilic pigment present in birds, fish and algae and it is
are believed to be inadequately efficient. This includes conditions such as more effective than other antioxidant agents e.g., vitamin E and carot-
chronic oxidative stress (Vaiserman et al., 2016) and aging, when per- enoid (Peng et al., 2014).
formance of endogenous antioxidant system in cell decreased. Hence, Plant-based phytomelatonin (PM) has antioxidant capacities and
centenarians are more affected by oxidative stress (Petruk et al., 2018). available as supplement (Ferri et al., 2019). Phytochemical antioxidants
Consequently, the combined effects of antioxidant-deficiency and have capability to fight against aging and the disorders associated with it.
malnutrition make individuals more susceptible to oxidative stress (Liu For example, coffee reduced both cognitive and motor deficits in aged
et al., 2018). rats because it contains high levels of antioxidant phytochemicals.
According to Harman's theory (Harman, 2006), exogenous antioxi- However, antioxidant phytochemicals have various mechanisms through
dant sources are very important to hamper the effects of oxidative stress. which they show anti-aging activities (Zhang et al., 2015a,b).
This includes beta-carotene, coenzyme Q10, vitamins E and C, lipoic According to the criteria of evidence-based medicine, long-term
acid, glutathione, coenzyme Q10, phytoestrogens, polyphenols, sele- clinical trials always demonstrated the ineffectiveness of antioxidants,
nium, zinc and manganese. Endogenous antioxidant depletion can be only with the exception of a few studies. Currently, there is little or no
halted by antioxidant supplementation, ultimately mitigating the asso- impact of antioxidant potions or pills on aging or human health, because
ciated oxidative damage (Liu et al., 2018). from billions of years antioxidant safety is an evolved system that resists
Fruits, vegetables, beverages, tea, coffee, spices, nuts, and cereal being easily tampered with (Schmidt et al., 2015; Gutteridge and Halli-
products are major sources of plant-derived antioxidants. These are pri- well, 2018).
marily phenolic compounds, vitamins, and flavonoids (Zujko et al., 2015) Although, the effects of endogenous antioxidants (glutathione, cata-
and alleviate cardiovascular disease, diabetes mellitus and numerous lase, superoxide dismutase) in protecting cells from aging by scavenging
other diseases (Miro
nczuk-Chodakowska et al., 2018; Khanthapok and free radicals is known but the role of exogenous antioxidant supplements
Sukrong, 2019; Suleman et al., 2019). against aging requires more investigations. Several studies have shown
A significant role is played by nutraceuticals and functional foods that the use of dietary antioxidant supplements cannot increase life span
having antioxidants in delaying the process of aging. A research per- in mammals (Wichansawakun and Buttar, 2019).
formed on different aging models has shown the prolonged lifespan by Another observation demonstrated that, though a healthy diet is
some antioxidants and dietary calorie restriction (Peng et al., 2014). recommended in preventing effects of oxidative stress and is considered
Coumarins and compounds having OH groups are more active for anti- indispensable but it remains poorly understood that what's the molecular
oxidant activity (Neha et al., 2019). Antioxidants have a heterogeneous mechanisms through which nutrients are capable of exerting antioxidant

8
U.-e.-A. Warraich et al. Heliyon 6 (2020) e04107

effects (Monti et al., 2019). One study reported that both catalase and 4. Conclusion
synthetic SOD increase life span of cells significantly (Abbas et al., 2017).
Based upon review of literature depicted in this article, antioxidants We all are aware of the fact that a high mortality and morbidity rate
can be classified as given in Table 1. are attributed to aging. Aging is a global issue as the number of cente-
narians increasing worldwide. We cannot deny the reality of being aged
3. Computational models but we can convert this time-dependent and natural process of aging, into
a healthy aging process by taking certain preventive measures, because
Almost all species are affected by aging. A variety of controlled ma- the number of healthy centenarians is not very high. As environmental
chine learning algorithms are used to understand the complexities of the parameters also contribute largely to aging so we should pay attention to
aging. A review of literature by data mining and machine learning has led regulating the ROS producing environmental factors. Similarly, our diet
to following inferences: 1) DNA repair has link to aging, 2) certain pro- should be rich in antioxidants such as fresh fruits and vegetables that may
teins have role in aging, 3) life span is associated with programmed cell help in preserving the equilibrium between oxidants and antioxidants
death, ions transport, membrane receptors, 4) many biomarkers of aging and ultimately healthy aging process. A lot of work is needed for the
exist. Machine learning algorithms have certain limitations too. Only one production of effective exogenous antioxidants from natural sources,
study verified computational machine learning data inferences with wet- though they cannot stop it but may lessen the process of aging hence
lab trials. Additional research of validation of results is required in future making it less bad or a healthy one. Future predictions regarding aging,
(Fabris et al., 2017). biochemical mechanisms involved, biomarkers internal and external
Classic theory of aging suggested that detrimental DNA mutations are factors can be easily done with machine learning algorithms and other
not eliminated by natural selection in older age. Another theory proposed computational models.
that genetic basis of aging is adapted to optimize evolutionary passage of
selection. By computer modeling (Markov et al., 2018), it was proposed Declarations
that intrinsic decline of some physiological processes enhances efficacy
of natural choices for other processes too. However, they could not Author contribution statement
elaborate the mechanisms that warrant the spread and sustenance of
age-related genes. All authors listed have significantly contributed to the development
ROS and numerous inflammatory processes stimulate neuro- and the writing of this article.
degeneration. Advanced computational biology techniques such as
CADD (computer aided design) has major contribution in development, Funding statement
characterization and testing of drugs against neurodegenerative diseases
such as Alzheimer's disease and Parkinson's disease. CADD was used in a This research did not receive any specific grant from funding agencies
study of secondary plant metabolites in molecular docking. Ligand- in the public, commercial, or not-for-profit sectors.
based-virtual screening (Random Forest) and structure-based- virtual
screening (docking of 469 alkaloids data set from family Apocynaceae Competing interest statement
was taken from data bank) were done to identify potential structures that
could inhibit acetylcholinesterase activity in human (Scotti and Scotti, The authors declare no conflict of interest.
2015).
In a study (Putin et al., 2016), a modular ensemble of 21 deep neural Additional information
networks (DNNs) of variable complexity, assembly and machine learning
(ML) technique support vector machines (SVM) were used to assess No additional information is available for this paper.
factors affecting human aging process. The model ensemble found that
albumin protein, blood glucose levels, enzyme alkaline phosphatase,
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