Advances in Bioscience and Biotechnology, 2012, 3, 705-711 ABB Published Online October 2012 (
The relationship between apoptosis and aging
Bin Lu1,2, Hong-Duo Chen1, Hong-Guang Lu2*
1Department of Dermatology, Affiliated Hospital of China Medical University, Shenyang, China
2Department of Dermatology, Affiliated Hospital of Guiyang Medical University, Guiyang, China
Email: *
Received 15 August 2012; revised 20 September 2012; accepted 29 September 2012
Apoptosis is involved in aging and age-related disease,
with respect to aging, apoptosis acting in a cell type-
specic manner. The rate of apoptosis is elevated in-
most types of aging cell populations and organs. In
stable cells and certain continuously dividing cells,
apoptosis serves to eliminate presumably dysfunc-
tional cells that show homeostatic failure due to oxi-
dative stress, glycation, and DNA damage, thereby
maintaining homeostasis in the body. What’s more,
apoptosis, at least in part, plays some important role
inthe regulation of aging process and anti-tumori-
genesis in mammals. Age-enhanced apoptosis may be
aninnate protective mechanism against age-associated
tumorigenesis. There is clear evidence to indicate that
senescent cells are remarkably resistant to apoptosis.
The intensity of global apoptosis and autophagy
clearance signicantly declines in humans during ag-
ing, as aging repress the apoptotic response. In this
paper, we will review the relationship between apop-
tosis and aging, and outline how are they interact
each other.
Keywords: Apoptosis; Aging; Senescence
Apoptosis is a process whereby cells activat e an intrinsic
cell suicide program that is one of the potential cellular
responses, such as differentiation and proliferation. It has
been dened in 1972 by Kerr et al. in contrast to necros is,
which is a cell death generally due to aggressions from
the external Medium [1]. Many theories of apoptosis
have been proposed, and they can be divided into intrin-
sic and extrinsic pathways. One of most important extrin-
sic pathways is radiation-induced apoptosis, that is con-
sidered to be one of the main cell death mechanisms fol-
lowing exposure to irradiation [2], especially ultraviolet
radiation b (UVB) [3]. The intrinsic pathways including
many hypothesis, and many factors involved in them,
such as gene [4,5], DNA damage [6], some proteins [7,
8], and kinases or phosphatases [9,10], lysosomes [11],
mitochondria [12], persistent stress [13], and ROS [14].
Apoptosis is a vital component of the evolutionarily con-
served host defense system of organisms. When sub-
jected to pathological attack, apoptosis is a guardian of
tissues, since it can cleanse of unt and injured cells
without evoking inammation [15]. In persistent stress,
such as in aging, increased apoptotic resistance can lead
to the survival of unfit cells that are not able to maintain-
proper housekeeping functions. This increase in apop-
totic resistance may be relevant if one considers the con-
text of tissue integrity during aging, but it takes place at
the cost of housekeeping potential and leads to a sense-
cent phenotype in post-mitotic cells.
Aging is an essential, inevitable physiological phe-
nomenon characterized by a progressive accumulation of
deleterious molecular damages in cells and tissues during
the post-maturational deterioration, which decreases the
ability to survive and increases risk of death [16]. The
aging process has many facets and multiple causes. The
primary molecular phenotype of aging is the stochastic
occurrence and accumulation of molecular damage lead-
ing to a progressive increase in molecular heterogeneity
and functional impairment [17]. Cellular senescence is
the state where cells have irreversibly lost their pro lifera-
tion ability, and they exhibit deficiencies in maintaining
their homeostatic processes [18]. The number of sense-
cent cells increases in tissues with aging. Many theories
about the causes of aging have been proposed [19], and
could be divided into two broad categories: the stochastic
theories and the developmental-genetic theories [20].
Age-related degeneration can be a consequence of a ge-
netic program or it may be an entropic process [21]. Ul-
timately, disorders in housekeeping ability jeopardize
homeostasis and expose cells to apoptotic forms of cell
Accumulating evidence strongly suggests that deregu-
lation of apoptosis is associated with the aging process
[22], however, it is still debatable whether aging sup-
presses or enhances apoptosis in vivo. At present, it is
unclear whether the alterations in apoptosis observed
*Corresponding a uthor.
B. Lu et al. / Advances in Bioscience and Biotechnology 3 (2012) 705-711
during ageing are consequences of ageing or participate
in the normal ageing process. In this paper, we will re-
view apoptosis application in ageing, and discuss what
role of apoptosis involved in aging process.
It has been elucidated that the possible role of apoptosis
in aging and age-related diseases [23]. Apoptosis, at least
in part, plays an important role in the aging process and
age-associated tumorigenesis in mammals [24]. The rate
of apoptosis is elevated inmost types of aging cell popu-
lations and organs, such as brain, cardio-vascular system,
immune system, endocrine system, intestine, reproduce-
tive system and eye [25]. Apoptosis increased in these
cells or organs is regarded as a protective mechanism of
the organism against an accumulation and spread of de-
fective cells, but the preponderance of this dismantling
system seems to highlight the age-associated decline and
deterioration in tissue and organ structure and function
[25]. Age-associated changes of the genes involved in-
apoptosis could be among the most prominent alterations
of gene expression in aging. On the one hand, lots of
genes promote apoptosis decrease in aging, such as the
gene of p53 and caspase family genes including Casp3,
Casp8, and Casp9 [26-29]. On the other hand, the ex-
pression of anti-apoptotic genes such as Bcl-2 was
upregulated in aging [26]. P53 functions as a longevity
assurance gene and a regulator of aging [3]. In several
mouse models, persistent low-level activation of p53,
either through deregulated expression of p53 itself or in
response to constitutive stress like DNA damage leads to
premature aging [30,31]. Members of the Bcl-2 family
proteins are critical death regulators that reside upstream
of antiapoptotic [32]. Either promoting apoptosis genes
decrease or anti-apoptotic genes decrease in aging proc-
ess, it can lead to aging in the end. So we deduce that
relationship of apoptosis and aging process is as follow-
ing: 1) Apop tosis is increased in most of organs with ag-
ing process; 2) Aging is able to restrain apoptosis to ap-
propriate states through genes or their products; 3) Aging
process is the result of the interaction of the apoptosis
and aging.
Changes in apoptosis have path-physiological cones-
quences in aging as a sentinel homeostatic pathway,
much apoptosis can yield tissue degeneration [33], while
little apoptosis allows either dysfunctional cells to accu-
mulate or differentiated immune cells topersist [34], and
inappropriate apoptosis may contribute to age-related
diseases and cancer [35]. It has been suggested that aging
related degenerative neurological diseases, such as Alz-
heimer disease [36] and Parkinson’s disease [37], and
that apoptosis is one of the underlying pathogenic me-
chanisms of these neurological diseases [38]. Amyotro-
phic Lateral Sclerosis (ALS) is an adult onset fatal dis-
ease. The feature of this disease is the degeneration of
motor neurons in the spinal cord and brain. Apoptosis
may play a role in this disease [39]. Huntington’s disease
(HD) is a progressive, fatal neurological condition, and
cells with mutant Huntington proteins may be more sen-
sitive to apoptosis induced by ageing associated oxida-
tive stress [40]. Other post mitotic tissues, like skeletal
muscle and heart, also exhibit age-related apoptotic ch-
anges [41,42].
It has been suggested that reprogramming cells to apop-
tosis may be a means to reduce cancer and eliminate one
cause of aging. An organism is constantly exposed to a
variety of stressful conditions. It would be disastrous for
the organism if it could not prevent the initiation of apop-
tosis when the initiation signal is due to reparable or mi-
nor damage. An important role of apoptosis is to ensure
the efficient removal of the cells whose continuing exis-
tence is detrimental to the organism [43]. Apoptotic de-
struction of a “unwanted” cell makes it ready for being
adhered and absorbed by a phagocyte [44]. The decline
in apoptotic response during aging could lead to loss of
phenotypic fidelity and a subsequent accumulation of
cells with macromolecular damage, including damage to
DNA [45]. Apoptosis protects against the accumulation
of pre-cancerous mutations by eliminating cells harbor-
ing excessive DNA damage [46]. Because non-senescent
old cells are still dividing, their apop tosis deficiency will
result in DNA replication past DNA lesions [47]. Apop-
tosis is also essential to wo und repair [48]. Wound repair
is impaired with aging [49]. During wound maturation,
fibroblasts need to be eliminated to reduce the produc-
tion of collagen and concomitant vascularity [48]. It is
noted that apoptotic fibroblasts are less abundant in the
dermal granulation tissue of older rats than in younger
rats [50]. It is possible that delayed skin wound repair of
older individuals is due, at least in part, to an apoptosis
defect in older fibr o bl ast s [4 7] .
Ageing has been described as one of the most potent-
carcinogens [51]. It is proposed that the sharp rise in
cancer incidence with age may be partly related to a sys-
temic failure of apoptosis [52,53]. Failure of cell death
programs at old age would be especially harmful for tis-
sues with retaining p roliferative ability and could explain
to some extent the well-documented increased incidence
of cancer and accumulation of DNA damage with age
[51]. Polyak et al. [54] observed a reduced apoptotic
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B. Lu et al. / Advances in Bioscience and Biotechnology 3 (2012) 705-711 707
response of lymphocytes to 5 Gy radiation in mice as they
aged, and Suh et al. [53] found a reduced apoptotic re-
sponse in rat liver cells exposed to methyl methane-sul-
phonate. Both of them discuss the possibility that the
sharp rise in cancer incidence with age may be partly
related to a systemic failure of apoptosis [52]. The dates
from mice also support the views that apoptosis are a de-
fense against cancer [30]. It is thought that apoptosis
may be protective against cancer in some tissues, and the
decrease in apoptosis with age because of less efficient
cellular signaling and regulation may promote cancer
ogenesis [55]. p53 is a potent initiator of both apoptosis
and cell cycle arrest, and the decline in p53 response to
stress at older ages in animals could contribute to the
observed dramatic increases in cancer incidence, and
provides a reasonable explanation for the correlation
between tumorigenesis and aging [56]. The decline in
p53 at older ages could contribute to the observed dra-
matic increases in cancer incidence [56]. It is certainly
possible that some of th e mutations which occur early in
tumor formation may increase the mutation rate and
lower the time to tumor formation and coun ter acting this
process is the p53-mediated elimination of clones of cells
via apoptosis that contain these mistakes [55]. Moreover,
numerous studies have indicated that anticancer therapies
primarily act by activating the apoptosis response path-
way in tumor cells [57-61].
Cellular senescence is the state where cells have ire-
versibly lost their proliferation ability, and they exhibit
deficiencies in maintaining their homeostatic processes
[18,62]. Senescent cells display a number of distinctive
characteristics, such as increased ROS production, in-
creased oxidative damage, increased glycation damage,
reduced heat shock protein expression, accumulation of
defective proteins tog ether with decline in apoptotic pro-
tein function [63]. If cells are unable to repair DNA
damage, apoptosis may ensue, followed by replacement
via division of another cell. Senescent cells are resistant
to apoptosis and more sensitive to cell injury [55], and
increased resistance toapoptosis is a significant func-
tional hallmark of senescen t cells. It is demonstrated that
replicative senescent human fibroblasts were resistant to
apoptotic insults. Moreover, fibroblasts of progeroid-
Werner syndrome patients exhibit attenuation of p53-
induced apoptosis [64], and p53-mediated gene expres-
sion is involved in the appearance of apoptosis resistance
in human skin fibroblasts [3]. Recently, it is reported that
the appearance of resistance to UVB-induced apoptosis
clearly precedes the progressive development of replica-
tive senescence inhuman fibroblasts [47]. Resistance to
apoptosis might partly explain why senescent cells are so
stable in culture, and it attribute might also explain why
the number of senescent cells increases with age [65].
However, it is still largely unclear whether age-related
cellular senescence and quiescence of mitotic cells can
elicit resistance to apoptosis in tissues, comparable to
apoptotic resistance in cultured cells. The problem seems
to be that apoptotic cells are not frequently encountered
in tissue sections, this probably being attributable to ei-
ther their fast clearance or to apoptotic resistance under
normal conditions.
The mechanisms by which senescent cells resist apop-
tosis are poorly understood. In some cells, resistance
might be due to expression changes in proteins that in-
hibit, promote or implement apoptotic cell death [66]. In
others, p53 might preferentially transactivate genes that
arrest proliferation, rather than those that facilitate apop-
tosis [67]. However, there are clear cell type-dependent
differences in the apoptotic resistance induced by growth
arrest and cellular senescence in cultured cells. For ex-
ample, senescent keratinocytes are resistant to UV-in-
duced apoptosis, as are skin fibroblasts [68], but senes-
cent endothelial cells are more vulnerable to apoptosis if
examined under in vitro cell culture conditions [69].On
the other hand, endothelial cells incultured arteries have
been reported to display an increased resistance to apop-
tosis in long-lived rodents [70]. One explanation could
be that senescent endothelial cells in culture undergo
anoikis, not apoptosis. Anoikis is a specific apoptotic
process triggered by the loss of extracellular matrix in-
teractions [71]. The mechanisms conferring resistance to
anoikis are quite different from those inhibiting apop-
As mentioned above, senescence in cultured cells resis-
tant to apoptosis, however, it is not clear whether tissues
or organizes can elicit resistance to apoptosis. The prob-
lem seems to be that apoptotic cells are not frequently
encountered in tissues, this probably being attributable to
either their fast clearance or to apoptotic resistance under
normal conditions. Recently, it is demonstrated that the
intensity of global apoptosis significantly declines in
humans during aging [72]. With increasing age there was
a decrease in apoptotic markers and pro-apoptotic factors
and an increase in anti-apoptotic factors in circulation
[72]. Moreover, several studies have demonstrated that
aging decreases the apoptotic response to genotoxic
stress [53,73]. Apoptosis is also involved in the age-re-
lated remodeling of the immune system, i.e., decreased
proliferation capacity and increased resistance to apop-
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B. Lu et al. / Advances in Bioscience and Biotechnology 3 (2012) 705-711
tosis [74]. De Martinis et al. [75] have described the cells
of the immune system undergo two different kinds of
apoptotic processes: activati on-i nduced cell deat h (AICD),
geared towards the elimination of unnecessary lympho-
cytes following clonal expansion, and damage-induced
cell death (DICD), particularly important for preventing
the onset of neoplastic proliferations. Organismal aging
seems to potentiate the apoptotic pathway of AICD and
decreases the sensitivity to DICD [75]. The apoptotic
deficiency in immuneosenescent lymphocytes can also
provoke autoimmune responses in the elderly. Lympho-
cyte senescence is probably one form of the rather com-
mon senescence-associated secretory phenoltype, and in
that way it supports the appearance of age-related pro-
inammatory status, which accelerates the aging process
and aggravates age-related degenerative diseases.
However, increased resistance to apoptosis of sense-
cent cells represents a threat to functional integrity, such
as the immune system, skin, and vascular endothelium.
Increased tolerance of cells to molecular damage leads to
the accumulation of intracellular waste products within
nondividing cells, e.g., senescent cells and post-mitotic
cells. This activates autophagocytosis, a major cellular
housekeeping mechanism that can remove damaged
molecules and organelles. However, many studies have
demonstrated that autophagy clearance declines during
the normal aging process [76,77]. Recent studies have
revealed that autophagy has an effect or role in the induc-
tion of the senescent phenotype [78-80] It is demon-
strated that autophagy is clearly activated during the
transition phase into cellular senescence in fibroblasts
[79,80]. The induction of autophagy in the early phase of
the accelerated aging process seems to be a survival
mechanism that compromises the metabolic disorders in
the transition phase in order to inhibit apoptotic cell
death [81] .
Apoptosis is involved in aging and age-related disease,
however, apoptosis serves to eliminate presumably dys-
functional cells and protect organism from cancer. On the
other hand, senescent cells are remarkably resistant to
apoptosis, what’s more, the intensity of global apoptosis
and autophagy clearance significantly declines in hu-
mans during aging, as aging repress the apoptotic re-
sponse. In conclusion, apoptosis is the reasonable result
of the aging process, and aging enhance the cells and
organisms apoptosis, however, aging process resist apop-
tosis as a crucial defense mechanism against sublethal
damage. On the other hand, apoptosis is benefit to aging
and aging process, as it is important to organ to maintain
homeostasis and protect against age-associated tumori-
genesis. Numerous studies have indicated that anticancer
therapies primarily act by activating the apoptosis re-
sponse pathway in tu mor cells, so apoptosis may be used
in exploring the mechanisms of tumorigenesis and anti-
cancer therapy.
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