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OUTLINE

 1.  Abstract
 2.  Keywords
 3.  1. Introduction
 4.  2. The oxygen paradox in aging
 5.  3. The mechanisms by which HBOT intervenes aging
 6.  4. Therapeutic implications of HBOT in aging intervention
 7.  5. Limitations and future directions
 8.  Author contributions
 9.  Declaration of competing interest
 10. Acknowledgments
 11. Abbreviations
 12. References

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REDOX BIOLOGY

Volume 53, July 2022, 102352



HYPERBARIC OXYGEN THERAPY FOR HEALTHY AGING: FROM MECHANISMS TO THERAPEUTICS

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ABSTRACT

Hyperbaric oxygen therapy (HBOT), a technique through which 100% oxygen is
provided at a pressure higher than 1 atm absolute (ATA), has become a
well-established treatment modality for multiple conditions. The noninvasive
nature, favorable safety profile, and common clinical application of HBOT make
it a competitive candidate for several new indications, one of them being aging
and age-related diseases. In fact, despite the conventional wisdom that
excessive oxygen accelerates aging, appropriate HBOT protocols without exceeding
the toxicity threshold have shown great promise in therapies against aging. For
one thing, an extensive body of basic research has expanded our mechanistic
understanding of HBOT. Interestingly, the therapeutic targets of HBOT overlap
considerably with those of aging and age-related diseases. For another,
pre-clinical and small-scale clinical investigations have provided validated
information on the efficacy of HBOT against aging from various aspects. However,
a generally applicable protocol for HBOT to be utilized in therapies against
aging needs to be defined as a subsequent step. It is high time to look back and
summarize the recent advances concerning biological mechanisms and therapeutic
implications of HBOT in promoting healthy aging and shed light on prospective
directions. Here we provide the first comprehensive overview of HBOT in the
field of aging and geriatric research, which allows the scientific community to
be aware of the emerging tendency and move beyond conventional wisdom to
scientific findings of translational value.

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KEYWORDS

Hyperbaric oxygen therapy
Aging intervention
Age-related disease
Oxidative stress
Cellular senescence


1. INTRODUCTION

Aging is characterized by a progressive loss of physiological functions over
time. Not only does aging substantially affect the quality of life, but it also
represents a major risk factor for a number of age-related diseases. Effective
approaches are required to sustain better health in old age by slowing down the
natural aging process and preventing age-related conditions. At present, there
are limited options to interfere with the aging process, such as stem cell
therapy, young plasma transfusion, physical exercise, intermittent fasting and
senotherapeutics [1]. These mainstream strategies have inspired great interest
in the scientific community and shown considerable promise in combating aging.
There are, however, a few flies in the ointment (Fig. 1). First, some of the
known therapies, such as young plasma transfusion and stem cell grafting,
involve a certain degree of invasiveness. Second, despite adequate safety,
lifestyle changes alone, such as physical exercise and intermittent fasting, may
not be sufficient to ensure definitive efficacy. Third, senotherapeutics, as
another modality of noninvasive strategy, are not yet fully understood in humans
and still in their infancy before routine clinical practice, mainly due to the
complex, time-consuming and expensive procedure of pharmacological development.
Therefore, while effectively advancing existing strategies, researchers are also
in search of novel strategies to achieve healthy aging that are noninvasive,
sufficiently effective, and easy to use, among which hyperbaric oxygen therapy
(HBOT) is a competitive candidate.

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Fig. 1. Potential strategies against aging and their deficiencies. Strategies
under development to intervene aging include stem cell therapy, young plasma
transfusion, physical exercise, intermittent fasting and senotherapeutics.
Despite the great promise of these mainstream strategies, there are three
deficiencies among them. (1) Stem cell transplantation and young plasma
transfusion involve a certain degree of invasiveness. (2) Physical exercise and
intermittent fasting alone may not be sufficient enough to ensure definitive
efficacy. (3) The efficacy of senotherapeutics is not yet fully understood in
humans and the development pipelines are complex, time-consuming and expensive.

HBOT is a noninvasive technique to allow 100% oxygen supplied at a pressure
greater than 1 atm absolute (ATA). The treatment was originally used for
conditions related to hypoxia [2]. Up to now, it has become a well-established
treatment modality for diverse conditions, including non-healing wounds,
infections and medical emergencies [3]. Through providing a sealed environment
with high pressure and rich oxygen, HBOT can effectively increase the oxygen
content dissolved in plasma and arterial oxygen partial pressure [4]. Oxygen is
a pivotal player in numerous physiological processes, reaching all tissues and
cells through blood circulation. Hence, HBOT can induce a wide range of
cellular, biochemical, and physiological changes throughout the body. Proven
biological mechanisms through which HBOT exerts its beneficial effects in
traditional indications include angiogenesis promotion, inflammation
alleviation, antioxidant defense enhancement, stem cell stimulation and so
forth. Nowadays, proposals for new indications for HBOT continue to arise, among
them are aging and age-related diseases, which draw our attention. As with most
established indications, the employment of HBOT in aging intervention is based
on its multiple effects on the organism. The advantages of HBOT as a novel
therapy for healthy aging include its noninvasiveness, established safety
profile and common clinical application in diverse populations [5]. This article
aims to provide an overview of the mechanisms by which HBOT targets the aging
process, as well as its potential therapeutic implications supported by
pre-clinical and small-scale clinical studies.


2. THE OXYGEN PARADOX IN AGING

There is a paradoxical relationship between oxygen and aging. Despite the
indispensable role that oxygen plays in tissue homeostasis and organismal
survival, oxygen is considered a key driver of the aging process as well. Before
we discuss the therapeutic mechanisms of HBOT in aging intervention, it is
necessary to delve into the delicate balance of protection versus damage by
oxygen in living organisms.

Oxygen serves as a source of reactive oxygen species (ROS). Though ROS can be
beneficial in some circumstances, overproduction of ROS is able to induce
cumulative macromolecular oxidative damage including lipid peroxidation, protein
dysfunction and DNA damage [6,7], all of which contribute to aging. Hence, it is
not surprising that hypoxic conditions can ameliorate multiple hallmarks of
aging in cell culture, including senescence-associated secretory phenotype
(SASP) production, mitochondrial dysfunction and replicative senescence [[8],
[9], [10]]. However, while it is often inappropriately assumed that the rate of
aging and oxygen levels are directly proportional, the biological consequences
of aging with respect to oxygen levels are actually complex and remain poorly
understood. As demonstrated in Drosophila, there is a non-linear response of
oxidative damage and lifespan to atmospheric oxygen levels [11]. Both extreme
high and low atmospheric oxygen levels lead to increased oxidative stress and
reduced longevity. On the other hand, a reduction in oxidative stress has been
attributed to both increases and decreases in oxygen levels [12,13]. In another
word, the truth is not a duality when it comes to the trade-off between hypoxia
and hyperoxia (Fig. 2), especially when issues such as free radicals, oxidative
stress and scavengers are involved [14,15]. There is actually a biphasic
response induced by HBOT: although the accumulation of ROS does exist, the
subsequent cytoprotective antioxidant responses tend to be more pronounced after
repeated exposures, which is discussed in detail in Section 3.3. In fact, it has
been already reported that systemic levels of oxidative stress are largely
unaltered in healthy young volunteers after multiple HBOT sessions, with signs
of depletion of ROS generation capacity [16]. Likewise, a recent study of HBOT
in middle-aged males reported attenuation of oxidative stress, as reflected by
circulating biomarkers [17]. These encouraging findings help alleviate concerns
that HBOT results in oxidative damage. More importantly, fluctuations in oxygen
concentration levels are perceived by tissues as a hypoxia trigger, allowing
HBOT over several cycles to stimulate cellular protection characterized by
hypoxia-inducible factor-1 (HIF-1) activation without additional detrimental
effects of hypoxia [18,19]. We will discuss this problem further in Section 3.1
and Section 3.3.

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Fig. 2. The biological consequences of aging with respect to oxygen levels. In
terms of aging, the truth is not a duality when it comes to the trade-off
between hypoxia and hyperoxia, especially when issues such as oxidative stress
and scavengers are involved. First, large deviations from normoxia (either
increases or decreases in oxygen levels) generally lead to increased oxidative
stress and reduced longevity. To the contrary, modest modulation of oxygen
levels (either increases or decreases in oxygen levels) can enhance the
antioxidant defenses and slow the aging process. These facts suggest both an
alert threshold in hypoxia and a toxicity threshold in hyperoxia in the
biological consequences of aging with respect to oxygen levels.

The contradictory roles of oxygen in aging can be attributed to the phenomenon
of “Hormesis”. The term describes the fact that treatment with sub-toxic and
non-damaging doses of a certain toxicant can actually induce adaptations that
prevent subsequent damage by the same agent [14]. The oxygen in HBOT may
represent such a sub-toxic substance. Doubtless, there exists a “toxicity
threshold” in terms of quantity and duration [20], beyond which oxygen
administration will speed up the aging process instead. The thresholds vary by
species, age and tissue, depending on the different cellular sensitivity to
oxygen. This would be helpful in explaining the seemingly paradoxical results
obtained under hyperoxic conditions in different settings. Together, we hold
that oxygen plays an active role against aging under appropriate protocols of
HBOT without exceeding the toxicity threshold. It forms the basis for our
subsequent discussion about the role of HBOT in the field of aging and geriatric
research.


3. THE MECHANISMS BY WHICH HBOT INTERVENES AGING

Substantial progress has been made in comprehending the molecular mechanisms of
the aging process over the past few decades. Obviously, this provides clinicians
with a wide array of therapeutic targets for aging and age-related diseases. At
the same time, there is growing evidence for the benefits of HBOT in tissue
homeostasis and regeneration. The fact that the therapeutic targets of HBOT
overlap considerably with those of aging and age-related diseases is beginning
to gain attention. In a recent prospective trial, HBOT was found to induce
transcriptome changes in whole-blood samples from healthy aging subjects, with
1342 genes upregulated and 570 genes downregulated [21]. Changes in these age
genetic signatures in vivo suggest remarkable effects of HBOT on the elderly, at
least at the molecular level. In this section, we aim to place HBOT in the
context of various aging theories and summarize possible mechanisms by which
HBOT promotes healthy aging (Fig. 3).

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Fig. 3. The mechanisms by which HBOT promotes healthy aging. HBOT can cause a
wide range of cellular, biochemical and physiological changes. The proven
biological mechanisms by which HBOT may promote healthy aging can be summarized
into five categories. (1) HBOT enhances angiogenesis mainly by increasing the
expression of HIF-1α and a series of angiogenic markers. (2) HBOT reduces
inflammation by regulating the number and activity of extensive inflammatory
cell types such as neutrophils, lymphocytes, astrocytes and microglia. At the
molecular level, HBOT can inhibit pro-inflammatory factors while promoting
anti-inflammatory factors. (3) HBOT enhances antioxidant defenses by modulating
the balance between free radicals and scavengers. The process is closely
correlated with the regulation of mitochondrial function. (4) HBOT interferes
with the detrimental effects of cellular senescence, manifested by cell cycle
re-entry and attenuation of senescence markers such as p16/p21/p53, SA-β-gal,
lipofuscin and the SASP. HBOT also plays a role in inhibiting telomere
shortening, one of the major stimuli of cellular senescence. (5) HBOT increases
the number of circulating stem cells by stimulating stem cell mobilization, and
changes stem cell properties by promoting proliferation and differentiation.


3.1. ANGIOGENESIS ENHANCEMENT

Impaired vascular homeostasis and angiogenesis, one of the hallmarks of aging,
leads to reduced capillary density throughout the body, which in turn
contributes to fading physical functions in the elderly [22,23]. The corollary
to this “angiogenesis hypothesis of aging” recommends pro-angiogenesis therapy
for symptoms and signs of aging [23]. Meanwhile, oxygen is essential for
angiogenesis. Exposure to oxygen increases angiogenesis in a dose-dependent
manner [24]. And the stimulus for angiogenesis seems not to be the increased
oxygen availability by itself, but to be most related to the pressure at which
it is delivered [25]. Thus, both the hyperoxia and pressure components of HBOT
play an indispensable role in promoting angiogenesis. To date, numerous studies
have reported the pro-angiogenesis effects of HBOT in different tissues with
compromised blood perfusion such as skin [[26], [27], [28], [29]], brain [[30],
[31], [32]], penile [33], bone [34], and even tumor [35,36]. These results
firmly establish the pro-angiogenesis effects of HBOT, implying its possible
advantages in preventing age-related microcirculation impairments.

The mechanisms of HBOT impacting angiogenesis have been explored in various
animal models. There is an age-related signaling decline in HIF-1, contributing
to the defective neovascularization with natural aging [37]. Interestingly, it
has been widely reported in the literature that HBOT induces an increase in
HIF-1 [38,39]. HIF-1, consisting of HIF-1α and HIF-1β subunits, is an essential
mediator of oxygen homeostasis, whose biological activity is determined by the
expression of HIF-1α subunit [40]. Hypoxia is the main regulator of its function
and activity. Aside from that, there are many other regulatory factors, among
which are free radicals including ROS and reactive nitrogen species (RNS) [41].
Correspondingly, there are generally two approaches to modulating HIF-1α by
HBOT. For one thing, a unique protocol of repeated intermittent hyperoxia
exposures, with a 5-min air break every 20 min, can induce some cellular
mechanisms usually induced during hypoxia, including the release of HIFs and
increase in their stability and activity [27,42]. This is because the return to
normoxia following a hyperoxia exposure results in fluctuations in the dissolved
oxygen, which are interpreted by tissues as a lack of oxygen though hypoxia does
not actually occur, namely the so-called “hyperoxic-hypoxic paradox” [19]. The
same applies to the general HBOT protocols since intermittent fluctuations in
oxygen occur between daily treatments [43]. For another, it has been widely
acknowledged that HBOT leads to elevated partial pressure of oxygen in blood and
tissues, which in turn increases the production of ROS [39,43,44] and RNS
[44,45]. The transiently increased ROS and RNS serve as signaling molecules to
stabilize HIF-1 in its active form [44]. Following the stabilization and
activation of HIF-1, HIF-dependent vascular endothelial growth factor (VEGF)
stimulation contributes to blood vessel formation directly [40,46,47]. In
addition to the commonly observed increase in VEGF after HBOT in the literature
[26,38,48,49], several reports have revealed other angiogenic markers induced by
HBOT, such as EGF, PDGF, CXCL10, IL- 1α, FGF-2 and SDF-1 [26,48]. These
angiogenic factors, especially the most prominent proangiogenic factor VEGF,
work together to activate vascular cells to promote angiogenesis and
arteriogenesis [50]. Among them, HIF-1-regulated VEGF and SDF-1 can also reach
the circulation and stimulate bone marrow-derived endothelial progenitor cells
(EPCs) mobilization and recruitment, thus promoting angiogenesis and
vasculogenesis [50,51], which has been demonstrated in human subjects receiving
HBOT [50,52,53]. Another nuclear factor E2-related factor 2 (Nrf2) signaling
pathway induced by HBOT has also been shown to stimulate angiogenesis, possibly
through its interaction with VEGF and other angiogenic factors [48].


3.2. IMMUNOMODULATORY PROPERTIES

Immune dysregulation and activation of inflammatory pathways have been
postulated to be essential contributors to tissue dysfunction in the course of
aging [54]. The chronic, sterile, low-grade inflammatory state during aging,
also known as inflammaging, plays a vital role in the pathogenesis of
age-related diseases. In recent years, interventions targeting inflammatory
pathways have shown great potential in the rejuvenation of different tissues,
thereby preventing age-related tissue dysfunction [54]. Coincidentally, HBOT has
shown its immunomodulatory properties from the beginning of its use, suggesting
its benefits in ameliorating age-related immune dysregulation.

At the cellular level, HBOT can exert immunomodulatory effects on a variety of
inflammatory cell types. Neutrophil apoptosis plays a crucial part in the
resolution of inflammation, while enhanced apoptosis of neutrophil-like cells is
observed after a single 90 min exposure to hyperbaric oxygen, as evidenced by
promoted caspase 3/7 activity and morphological changes associated with
apoptosis [55]. In another study, neutrophils from severely injured patients or
healthy volunteers respectively showed no significant reduction in apoptosis but
a decline in ROS production, MAPKs activation and NETs release after exposure to
hyperbaric oxygen [56]. Despite the contradiction, both in vitro studies suggest
a role for HBOT in limiting neutrophil-mediated systemic inflammation. This has
been confirmed by in vivo experiments using different animal models, in which
HBOT reduces neutrophil recruitment and activation [57,58]. Apart from its
effects on neutrophils, hyperbaric oxygen can induce the apoptosis of
lymphocytes as well via a mitochondrion-associated mechanism, demonstrated by
caspase-9 activation and loss of mitochondrial membrane potential [59,60].
Besides, HBOT can reduce inflammation by regulation of iNOS activity/expression
and nitrite/nitrate production in lymphocytes, as observed in T1DM patients
[61]. These results illustrate that HBOT suppresses lymphocyte-mediated
inflammatory responses both quantitatively and qualitatively. For T lymphocytes,
a single exposure to hyperbaric oxygen can result in a transient reduction in
the CD4:CD8 ratio in blood from healthy volunteers [62], reinforcing the role of
HBOT in reversing immunosenescence as an augment in the CD4:CD8 ratio with aging
was previously reported in human peripheral blood [63,64]. The brain is known as
an immune-privileged organ, in which astrocytes act in concert with microglia in
neuroinflammation during normal aging, leading to cognitive impairment [65].
HBOT can attenuate neuroinflammatory processes by reducing astrocytes and
microglia activation in different animal models including aging [66],
Alzheimer's Disease (AD) [67] and brain injury [68]. These results confirm that
HBOT's effects on inflammatory cells are not limited to those in the blood
circulation.

At the molecular level, HBOT can target the inflammatory process through its
extensive effects on the expression of cytokines and other mediators. Various
pro-inflammatory cytokines and inflammatory mediators are reduced in the
peripheral blood following HBOT, including IL-1β, IL-2, IL-6, TNF-α, IFN-γ,
PGE2, COX-2 [60,[69], [70], [71], [72]]. The same goes for the levels of
inflammatory markers in different tissues. Meanwhile, HBOT can lead to increases
in some anti-inflammatory cytokines, including IL-1Ra, IL-4 and IL-10
[48,67,[72], [73], [74]]. Among them the most frequently reported is IL-10, the
major mediator of protective effects of HBOT against sepsis [75] and traumatic
brain injury [76]. There are conflicting results pertaining to acute phase
proteins [77], with most reports showing a decrease in CRP while a few showing
stimulation of G-CSF and inhibition of IGF-1. As an overall effect, it has been
reported that HBOT can exert protective effects against multi-organ damage
following generalized inflammation [78]. Mechanisms include that hyperbaric
oxygen can interfere with the TLR/NF-κB pathway, accounting for a downregulation
of pro-inflammatory cytokine release [78]. Given that the aging process is
accompanied by the activation of multiple inflammatory pathways throughout the
body, the results suggest that HBOT may protect various tissues from chronic
inflammatory damage during aging in a similar manner.

Collectively, HBOT appears to exert anti-inflammatory effects in a variety of
both physiological and pathological conditions. So far, researchers have
preliminarily observed benefits of HBOT in slowing down tissue aging by
attenuating inflammation, while more comprehensive research is expected to
clarify the systemic effects of HBOT on age-related inflammatory state.


3.3. ELEVATION OF ANTIOXIDANT ACTIVITY

Oxidative stress is induced when ROS production exceeds antioxidant capacity.
The oxidative stress theory of aging takes it as a major mechanism responsible
for age-related functional losses and longevity limitation. At the same time,
the decrease in mitochondrial efficiency plays a significant role in oxidative
stress induced with aging [79], since mitochondrion is a primary site for ROS
production in the cell. We have summarily described the biological consequences
of excessive oxygen on oxidative stress and antioxidant defense in Section 2. In
this section, we discuss in detail the role of HBOT on oxidative stress balance,
as well as its effect on mitochondrial function (Fig. 4). We will pay particular
attention to the antioxidant potential of HBOT when applied appropriately as an
alternative theoretical mechanism.

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Fig. 4. The effects of HBOT on oxidative stress balance and mitochondrial
properties. In HBOT, the inhaled oxygen passes through the lungs, effectively
elevating the content of oxygen dissolved in the plasma, which in turn causes a
plethora of oxygen within tissues. In mitochondria of tissue cells, the citric
acid cycle is boosted under hyperoxia. NADH, a product of the citric acid cycle,
can react directly with oxygen to produce ROS in the mitochondria. The
overproduced ROS activates HIF-1α, which conjugates with HIF-1β to stabilize
HIF-1 in its active form (Another way HBOT stabilizes HIF-1 arises from the
hypoxic-like state during intermittent periods). HIF-1 inhibits mitochondrial
biogenesis. On the other hand, consumption of more NADH by mitochondria results
in higher NAD + levels. In the presence of elevated NAD+, SIRT1 is activated,
which improves mitochondrial biogenesis via acetylation of PGC-1α and induces
antioxidant responses via deacetylation of FOXO3a. Notably, as an adaptive
mechanism, high ROS levels can produce more endogenous scavengers as well. The
elimination half-life of scavengers is much longer than that of ROS, underlying
the antioxidant effects of HBOT. The molecular mechanisms by which HBOT
stimulates antioxidant defenses include activation of Nrf2 and its downstream
targets such as HO-1, NQO-1, CAT, GPx, SOD and GCLC, as well as decreased
expression of pro-oxidant enzymes such as iNOS and gp91-phox.

Under different protocols and pathological conditions, studies over the past few
decades on the effects of HBOT on mitochondrial properties and oxidative stress
balance have yielded mixed results [43]. On the one hand, HBOT is thought to
cause excessive ROS production and induce oxidative stress, implying adverse
effects while being therapeutic under certain circumstances [77,80]. This is
accompanied by a reduction in mitochondrial function [81]. On the other hand,
HBOT has been found to improve mitochondria activity as well as increase free
radical scavengers, thereby providing effective antioxidant defense
[13,17,43,48,49]. Despite the multifactorial process, the contradiction has
mainly been attributed to the number of sessions [43]. Generally, a single
exposure to hyperbaric oxygen or short-term HBOT may create oxidative stress.
Via mitochondrion-dominated mechanisms, HBOT leads to elevated ROS production.
Although there is an increase in scavenger production as an adaptive response to
ROS accumulation, the compensation is inadequate and gradual after limited
exposures [19]. In parallel, mitochondrial respiration is reduced in order to
counteract additional ROS production [81]. Sirtuin1 (SIRT1) is considered a
major metabolic stimulator of mitochondrial biogenesis and part of a cellular
defense mechanism against oxidative stress [82,83]. Its reduction with aging
contributes to age-related disorders. After repeated intermittent hyperoxia
exposures or long-term HBOT, SIRT1 is significantly activated through increased
NAD + levels from the hyperoxic state during HBOT [84,85], improving
mitochondrial biogenesis via acetylation of PGC-1α and inducing antioxidant
responses via deacetylation of FOXO3a [19]. Notably, HIF-1, which is also
activated after HBOT as described in Section 3.1, antagonizes the promoting
effect of SIRT1 on mitochondrial biogenesis [86]. The crosstalk between the
HIF-1α and SIRT1 pathways in HBOT remains to be further elucidated.
Synergistically with SIRT1-mediated beneficial effects, there is a distinct
increase in scavenging activity induced by ROS production following repeated
exposures, while the elimination half-life of scavengers is much longer than
that of ROS [19]. The biphasic response has been confirmed by a study revealing
that HBOT-induced DNA damage can only be detected immediately after the first
treatment but not after subsequent treatments under the same conditions,
suggesting that repeated exposures can result in an increased antioxidant
protection but not an accumulation of oxidative damage [87]. Taken together,
contrary to short-term protocols, long-term HBOT or repeated intermittent
hyperbaric oxygen exposures can enhance antioxidant defenses via adaptive
mechanisms. Apart from that, exposure pressure and frequency have been proposed
as important factors to consider when investigating antioxidant responses
induced by HBOT [88]. The contributions of variables other than the number of
sessions warrant further investigation.

Mechanistically, HBOT activates a series of transcription factors and gene
expression to increase endogenous antioxidant enzymes [13]. Nrf2, a redox
sensor, represents the master regulator of cellular defenses against oxidative
stress [89]. The age-dependent decline in antioxidant enzyme responses is
supposed to result from decreased expression of Nrf2 and its target genes [90].
Accumulating data suggest that HBOT induces antioxidant responses by
upregulating Nrf2 and its downstream targets, such as HO-1, NQO-1, CAT, GPx, SOD
and GCLC [48,[91], [92], [93]]. Reversal of age-related decline in Nrf2
signaling by HBOT makes it a viable therapeutic option for aging of the
antioxidase system. Besides increased expression of antioxidant enzymes,
decreased levels of enzymatic pro-oxidants, such as iNOS and gp91-phox, have
also been observed in two separate studies [74,94]. In conclusion, HBOT induces
an increase in antioxidant enzymes and a decrease in pro-oxidant enzymes through
a negative feedback, thereby enhancing the antioxidant defenses.


3.4. SUPPRESSION OF CELLULAR SENESCENCE

The accumulation of senescent cells in various tissues is regarded as a
significant contributor to aging as well as age-related diseases. Meanwhile,
cellular senescence can be characterized by multiple features, which have
emerged as potentially effective targets for therapeutic exploitation [95]. Here
we review the effects of HBOT on cellular senescence from multiple perspectives.

So far, no single marker with absolute specificity for senescent cells has been
established [96]. Two classic tools to identify senescent cells in vivo include
senescence-associated beta galactosidase (SA-β-gal) and cyclin-dependent kinase
inhibitors including p16 and p21 [97]. Intriguingly, in two independent reports,
HBOT respectively showed its ability to attenuate aging markers in the
hippocampus of d-galactose (D-gal)-induced aging mice, as demonstrated by
decreased number of SA-β-gal positive cells [66] and reduced expression of key
components of the senescence program, such as p16, p21 and p53 [71]. It has also
been shown that HBOT can reduce the number of SA-β-gal positive cells in
cardiomyocytes in aging pre-diabetic rats [98]. In another study, researchers
evaluated cellular senescence by lipofuscin, another established biomarker, and
found senescent cells cleared from skin after HBOT [27]. However, new indicators
for senescence such as LINE1 have been recently developed [99], which are absent
from existing HBOT studies. Besides, a multi-parametric strategy for
identification of senescent cells is currently being advocated [96]. For
example, the use of SA-β-gal assay in combination with nuclear HMGB1 staining
allows a more accurate evaluation of senescence than SA-β-gal staining alone
[100]. Therefore, the pleiotropic phenotypes of senescent cells have not been
considered in the existing literature, which is clearly a limitation.

In tissues, senescent cells are heterogeneous but share a number of common
features, among which the most widely recognized are the permanent cell cycle
arrest and a bioactive secretome, namely the SASP [97]. Critical components of
pathways involved in senescence-mediated cell cycle arrest include p16, p21 and
p53 [101], which, as noted above, tend to decrease after HBOT [71], reflecting
the potential of HBOT to resume cell cycle progression in senescent cells. In
prostate cancer cells, a single exposure to hyperbaric oxygen causes senescent
cells to enter cell cycle [102]. Likewise, exposure to hyperbaric oxygen can
prevent cell cycle arrest in malignant glioma cells [36]. Nevertheless, the
current results are insufficient to illustrate the general effects of HBOT on
senescent cells, as cancer cells are more likely to overcome the
senescence-associated cell cycle arrest. Senescent cells secrete the SASP, which
usually consists of pro-inflammatory cytokines and chemokines, angiogenic
factors, growth factors, and matrix metalloproteinases (MMPs) [96,97]. The
downregulation of a variety of factors involved in the SASP after HBOT has been
described in Section 3.1 and Section 3.2. Moreover, the declined expression of
MMPs after HBOT has also been well documented [94,103,104]. Therefore, there is
sufficient evidence to support the role of HBOT in blocking SASP. Since
development of the SASP can partially explain the deleterious, pro-aging effects
of senescent cells [96], the downregulation of SASP expression by HBOT may
alleviate the pro-aging effects of senescent cells to a certain extent, or more
optimally, reflect the result of senescent cell clearance. In general, specific
therapies to target senescent cells are referred to as senotherapeutics,
consisting of senomorphics and senolytics [105]. The former indirectly impedes
the appearance of senescence phenomenon through blocking the SASP, while the
latter selectively clears senescent cells [100,106]. Some of them have been
shown to markedly intervene with the aging process in animal models. In
practice, however, only a few senolytics have entered early-stage clinical
trials, while senomorphics have yet to enter clinical trials with greater
potential risks [105]. It seems that the role of HBOT coincides with theirs in
intervening in cellular senescence. To some extent, this raises the possibility
that HBOT can be utilized as an available alternative to senotherapeutics, or as
an adjunct therapy.

One of the major pro-senescence stimuli is telomere shortening [97], which can
be either a direct inherited trait or the result of multiple environmental
factors [42]. Telomere length in blood cells is a proxy for telomere length in
various tissues and thus a useful biomarker of human aging [107]. For divers
exposed to intense hyperbaric oxygen, a previous study showed telomere
elongation in leukocytes over a 12-month interval [108]. Similarly, a recent
clinical trial in healthy aging populations has revealed that HBOT can target
cellular senescence in isolated leukocytes in terms of telomere shortening and
accumulation of senescent cells [42]. Unfortunately, neither telomerase activity
nor the expression of CD57, the most reliable surface marker for T cell
senescence, was evaluated in this study, complicating the interpretation of the
results. In addition to the effect of HBOT on circulating immune cells, the
restoration of telomere length was also observed in the hippocampus after HBOT
in aging and obese rats with shortened telomeres [66]. By and large, HBOT makes
a difference in inhibiting telomere shortening, but it remains to be clarified
how hyperbaric oxygen targets telomeres and how its response relates to
different conditions.

It appears to be an attractive rationale to blunt the pro-aging effects of
senescent cells with HBOT. At the present stage, the study on understanding the
role of HBOT in senescent cells is still in its infancy, but with rapid
progress. Future work is essential and expected to examine suitable biomarkers
of cellular senescence. Given the diversity of senescent cells of different
origins, it is necessary to evaluate the effects of HBOT on cellular senescence
in various systems in vivo.


3.5. STEM CELL REGULATION

Stem cell can promote tissue regeneration not only by replacing dead cells with
new ones, but also by secreting cytokines and growth factors, making them prime
targets in aging and regenerative medicine. Based on that, an attractive theory
of aging holds that the loss of stem cell number and activity over time drives
organismal aging [109]. Interestingly, studies in various tissues and diseases
have established stem cells as key players in the regenerative effects of HBOT.
It can be inferred that regulating stem cell biology to slow aging by HBOT may
be feasible in at least three aspects.

First, HBOT can stimulate stem/progenitor cell (SPC) mobilization and
recruitment from bone marrow. As described in Section 3.1, HBOT mobilizes SPCs
by stimulating NOS, increasing its circulating population and intracellular
regulatory protein content [52,110]. The mobilized SPCs have been found to be
engaged in wound healing [110,111] and cognition enhancement [112,113]. Second,
HBOT can cause changes intrinsic to SPCs, including the promotion of stem cell
proliferation and differentiation, as well as the regulation of protein
secretion. In vivo, HBOT has been reported to stimulate proliferation of neural
stem cell [114,115] and intestinal stem cell [116], growth and differentiation
of vasculogenic stem cell [117], and activation of colonic stem cells [118]. In
vitro, HBOT can promote proliferation and differentiation of adipose-derived
stem cells [119], as well as osteogenic and vasculogenic differentiation of
mesenchymal stem cells (MSCs) [120,121]. The secretion profile of proteins is
also modulated by HBOT in MSCs, with some upregulated proteins being
neuroprotective and others involved in cellular mechanisms against oxidative
stress [122]. While the above two mechanisms potentially ensure the efficacy of
HBOT alone by stimulating inherent stem cells, the third mechanism we summarize
here is that combining HBOT with stem cell transplantation can enhance the
therapeutic value of stem cells. Compared with monotherapy, a combined treatment
of stem cell transplantation and HBOT has shown better therapeutic effects on
cardiac regeneration [123], neurological function recovery [124], and metabolic
control [125]. Considering the great promise of stem cell transplantation in
aging or geriatric medicine, it is speculated that HBOT can be used as an
adjunct therapy to improve survival and function of the transplanted stem cells.
Despite the encouraging findings, research gaps in the effects of HBOT on stem
cell properties in the elderly are worth filling through continued studies in
the future.


4. THERAPEUTIC IMPLICATIONS OF HBOT IN AGING INTERVENTION

Supported by the multiple mechanisms described above, the past decade has seen
an explosion of interest in the rejuvenation potential of HBOT that goes far
beyond its traditional use in medicine. We hereby set out to review the
potential therapeutic implications of HBOT in aging intervention from the
existing literature (Fig. 5).

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Fig. 5. The effects of HBOT on aging in different organs or tissues. In
pre-clinical and clinical investigations, HBOT has shown great potential in
improving cognition, inhibiting intrinsic skin aging and photoaging, improving
glucose metabolism (by increasing thermogenesis and volume of brown adipose
tissue and promoting oxidative ability of skeletal muscle), preventing bone and
muscle loss, and enhancing myocardial and pulmonary function. (For
interpretation of the references to colour in this figure legend, the reader is
referred to the Web version of this article.)


4.1. COGNITIVE IMPROVEMENT

As the largest consumer of oxygen, the brain comprises only 2% of the body's
weight and yet utilizes 20% of the total oxygen and consumes 25% of the total
glucose [126]. Considering the importance of oxygen to the brain, researchers
have displayed great interest in applying HBOT to neurological disorders.
Cognitive decline begins as early as the third decade even in the absence of
pathologic neurodegeneration, making it a symbol of both healthy and
neurodegenerative brain aging [126]. Here we review the role of HBOT in
cognitive improvement, especially in the context of normal aging as well as
neurodegenerative brain aging.

Early studies showed that transient oxygen administration to healthy young
adults, even at normobaric conditions, significantly enhances cognitive function
through increased brain activation, as tested by different cognitive measures
including word recall [127], n-back task [128], visuospatial task [129], verbal
cognitive test [130], etc. Later, HBOT emerged as a novel approach to
temporarily enhance cognitive function in healthy adults. It was reported that
HBOT could improve memory performance in young healthy adults [131]. In another
study including healthy adults aged 22 to 68, HBOT significantly improved
cognitive, motor as well as multitasking performance [132], implying that HBOT
benefits the brain beyond what was previously known. The study was further
continued by the same team to examine the effects of HBOT on major cognitive
domains, with the most pronounced enhancement of episodic memory [133]. On the
other hand, some other measured cognitive domains yielded neutral results,
consistent with previous studies on single oxygen exposure that not all
cognitive domains can be improved by oxygen administration [127,134].

Back in 1970s, researchers first investigated the effects of HBOT on cognitive
impairment in the elderly, with conflicting results though [135,136]. Only in
recent years have researchers begun to refocus on the cognitive protective
effects of HBOT in the context of normal aging. It is widely acknowledged that
D-gal-induced model can mimic natural aging associated with neurodegeneration
[137]. In D-gal-induced preclinical aging model [66,71,138] or combined model of
D-gal-induced aging and obesity [66], HBOT has shown the ability to prevent
cognitive impairments and attenuate hippocampal pathologies. The demonstrated
mechanisms include improvement of cholinergic and anti-apoptotic functions
[138], inhibition of oxidative damage and inflammatory responses [66,71], as
well as modulation of age-related gene expression [71]. However, despite the
convenience of D-gal-induced aging model compared with naturally aging model, a
meta-analysis of D-gal-induced brain aging models reported significant
heterogeneity between studies on neurobehavioral and neurochemical outcomes
[139], suggesting that such results should be interpreted with great caution.
Despite the flaw, attempts have been made to apply HBOT to improve cognition in
the aging populations. In a randomized controlled trial involving 63 healthy
aging subjects, HBOT, utilized in a repeated 60 daily sessions protocol, was
shown to induce cognitive enhancements in clinical aspects including attention,
information processing speed and executive functions, likely by an increase in
regional cerebral blood flow (CBF) [140]. It's worth noting that the study
excluded transient effects of oxygen, as all changes were evaluated at 1–2 weeks
after the last session. The increase in CBF was later confirmed by another study
of HBOT in elderly individuals suffering from significant memory loss [141].

Over the years, studies investigating the effects of HBOT on various
neurological disorders including traumatic brain injury [32], anoxic brain
damage [142], and stroke [143], have provided satisfactory neurotherapeutic
effects, one of which is enhanced cognitive function. Of particular relevance to
the current review, apart from being a direct cause of the chronological
cognitive decline, aging is also the greatest risk factor for dementia [144],
which is characterized by pathological and progressive cognitive decline. Among
the various types of dementia, AD is the most prevalent one, followed by
vascular dementia (VD) [144,145]. To date, mounting evidence has supported the
notion that HBOT should be considered an effective treatment for both AD
[67,141,146,147] and VD [145,148], given the desirable cognitive-improving
results in animal models and clinical trials. Interestingly, the pathology and
biochemistry of late-life dementia, especially AD, share some common features
with those of normal aging [149,150]. We also note in the literature that the
effects of HBOT in dementia somehow resemble those in normal aging, such as
attenuating neuroinflammation [67] and increasing CBF [141], which further
confirms the benefits of HBOT for the aging brain, in both physiological and
pathological settings.


4.2. SKIN REJUVENATION

Unlike other organs of the human body, skin aging is not only inevitably
affected by the intrinsic aging process, as happens in all tissues, but also
subject to the unique process of extrinsic aging or photoaging, resulting from
exposure to environmental agents, particularly ultraviolet (UV) radiation
[27,151]. Photoaged skin has several clinical and histologic manifestations
distinct from those of intrinsic aged skin [151]. Here, we review the role of
hyperbaric oxygen in skin rejuvenation in terms of intrinsic aging and
photoaging respectively.

Like any other tissue, the intrinsic physiological aging of the skin is
accompanied by the accumulation of senescent cells [151]. Moreover, the dermis
of intrinsically aged skin shows degradation of collagen and elastic fibers
[152], as well as diminished blood supply [153]. A recent clinical trial
demonstrated that repeated intermittent hyperbaric exposures had dramatic
aging-modulating effects on the skin, illustrated as decreased senescent cells,
increased elastic fiber length and stability and collagen density, and induced
angiogenesis [27]. Notably, this study focused on intrinsic aging by taking skin
biopsies from a light protected area. The increase in angiogenesis and collagen
density was in line with previous reports of HBOT in skin conditions including
wound healing [26,28] and compromised grafts and flaps [29]. In the epidermis,
the intrinsic physiological aging can be characterized by a generalized
epidermal atrophy [151] mostly due to a decrease in proliferative activity and
turnover rate of epidermal basal cells [152,154]. It is reported that exposure
to mild hyperbaric oxygen with 36% oxygen reversed the age-related decline in
proliferative activity of epidermal basal cells in the skin of aged mice [154].
These results supported the point that the intrinsically aged skin can be
partially revitalized by hyperbaric oxygen, whose potentiality has not been
sufficiently realized.

In contrast to intrinsic aging, photoaging is featured by a thicker skin, with
deep marked wrinkles and irregular pigmentation [155]. Photoaging of the skin is
mostly attributable to UV irradiation, particularly UVA and UVB. UVA
(320–400 nm) have a strong penetrating ability, interacting with both epidermal
keratinocytes and dermal fibroblasts [156]. Pretreatment with HBOT protected
skin from UVA-induced oxidative damage in a mouse model, manifested by
reductions in apoptosis and proliferation of the skin, as well as prevention
from deleterious structural changes such as creasing and decreased elasticity
[157]. As a highly energetic component of UV light, UVB(280–320 nm) are the
major environmental threat to the skin, increasing the risk of long-term damage
[156]. A previous study found that exposure to hyperoxia (90% oxygen)
immediately after UVB irradiation attenuated acute UVB-induced skin angiogenesis
and wrinkle formation in adult mice [158]. Moreover, in healthy individuals, it
was reported that hyperbaric exposure at 1.25 ATA with 32% oxygen led to both
the fading in melanin pigmentation induced by UVB irradiation and the decrease
in senile spot size [159]. Taken together, high oxygen concentration has
demonstrated surprising potential in treatment of skin photoaging.

It is worth noting that strictly speaking, some of the studies mentioned above
involving hyperbaric exposure with moderate atmospheric pressure and oxygen
concentration [154,159] or simply hyperoxic exposure [158], are actually beyond
the definition of HBOT. Yet these studies have confirmed the importance of
oxygen to revitalize the aging skin. Up to now, the role of HBOT in skin aging
has not been fully understood. More supporting evidence is needed to determine
how high oxygen concentration affect the aging skin from every aspect of
intrinsic and extrinsic aging both clinically and histologically. Given the
varying test conditions in the existing literature, it is also necessary to
figure out the optimal atmospheric pressure, oxygen concentration and time of
treatment for maximal skin benefit. However, with the few positive outcomes, the
use of HBOT or hyperoxia conditions for skin rejuvenation has turned out to be
promising and effective, at least to a certain extent.


4.3. METABOLISM REGULATION

It has been commonly accepted that aging is associated with a loss of metabolic
homeostasis and plasticity. Accordingly, greater metabolic diseases incidence
rate estimates have been also observed in the elderly. The main mechanism of
HBOT includes the regulation of oxidative stress balance, which is closely
related to the pathogenesis of age-related metabolic conditions. Therefore, the
effects of HBOT on metabolic parameters, especially glucose metabolism, have
been extensively addressed in recent years.

Glucose homeostasis depends on appropriate insulin secretion and the sensitivity
of receptors to insulin, both of which are impaired with advancing age [160] In
two studies involving animal models of D-gal-induced aging and combined model of
D-gal-induced aging and obesity, HBOT attenuated disturbances of glucose
metabolism, mediated by restored insulin sensitivity instead of enhanced insulin
secretion [66,98]. In another study, following a reduction in AGEs, the levels
of TNF-α and IL-6, independent biomarkers predicting the development of insulin
resistance and type 2 diabetes mellitus [161], were decreased significantly
after HBOT in D-gal-induced aging mice [71]. To the best of our knowledge,
however, no clinical trials to date have tapped into the effects of HBOT on
glucose metabolism in healthy aging populations. In existing clinical trials
involving healthy individuals of a wide range of ages, HBOT has shown a tendency
to lower serum insulin [162], increase peripheral insulin sensitivity [163] and
reduce HbA1C [163], indicating that HBOT modulates glucose metabolism by
increasing insulin sensitivity in healthy adults [162]. Meanwhile, no
significant reduction in blood glucose levels was observed in those studies,
implying a low risk of hypoglycemia when HBOT was applied to individuals without
diabetes [163,164]. Given the age-related impairments of insulin sensitivity in
humans [160], these findings, along with the results from animal models of
aging, indicate that HBOT may benefit the aging populations in terms of glucose
metabolism by attenuating age-related insulin resistance.

In addition to the possible positive effects on glucose metabolism during normal
aging, HBOT has shown clinical efficacy in lowering blood glucose and improving
insulin sensitivity in type 2 diabetes mellitus [[164], [165], [166], [167]],
the most common age-related metabolic disorder. Notably, the majority of
participants in these studies received HBOT for treatment of diverse conditions
including non-healing ulcers and diabetic foot ulcers, leading to an older age
range [165]. It suggests that these conclusions may be more applicable to the
elderly diabetic population. Relevant mechanisms by which HBOT improves glucose
metabolism, as shown in animal models, include enhancements in oxidative
capacity and GLUT4 expression in skeletal muscle [168,169], as well as increases
in brown adipose tissue volume and thermogenesis by upregulating protein levels
of UCP1 and PGC−1α [168,170]. Moreover, HBOT has been proven to be beneficial
for treating diabetic kidney disease (DKD) in animal studies [171,172] and
preliminary clinical trials [173,174]. Considering the well-established role of
HBOT in diabetic foot ulcers, along with the potential benefits of HBOT on blood
glucose and DKD, there is a strong case for further research on role of HBOT in
treatment and prevention of the development of diabetes mellitus.

Insulin resistance is often accompanied by central obesity, hyperglycaemia,
dyslipidaemia and hypertension, collectively known as a pathological condition
called metabolic syndrome, which is also common in the elderly. In rats with
metabolic syndrome, apart from enhanced insulin sensitivity, researchers also
observed improvements in biochemical parameters of dyslipidemia after HBOT
[175,176] or exposure to mild hyperbaric oxygen [169], consistent with the
alternations of lipid profiles in diabetic subjects receiving HBOT [166,177].
Interestingly, HBOT also ameliorated obesity by reducing adipocyte hypertrophy
in rats with metabolic syndrome [175] and diabetic rats with obesity [178], and
in the former even significantly decreased body weight together with abdominal
and epididymal fat [175]. However, no effect on lipid profile or body weight was
observed in reports of aging or aging-obese rats [66,98]. It is unclear whether
this contradiction is due to the assumption that diabetic rats are more
sensitive to the effects of HBOT on lipid metabolism and obesity, or simply due
to the differences in experimental methods.

Collectively, HBOT has shown potential in alleviating impaired insulin
sensitivity in normal aging and age-related metabolic conditions including type
2 diabetes mellitus and metabolic syndrome. These findings are going to be the
basis for further work on detailed effects of HBOT on age-related metabolic
alternations.


4.4. MUSCULOSKELETAL RESTORATION

Musculoskeletal aging, resulting from various age-related changes in body
composition, inflammation and hormonal imbalance, is closely correlated with
high morbidity and healthcare rates in the elderly. In recent years, researchers
have demonstrated that mild hyperbaric oxygen under 1.25 ATA with 36% oxygen,
can be effective against degenerative changes in the musculoskeletal system. The
rodent model of hindlimb unloading, which was developed to simulate microgravity
conditions, has become a commonly used method for modelling a natural decrease
in muscle mass defined as sarcopenia [179,180], as well as disuse osteoporosis
frequently found in the bedridden elderly [181]. Exposure to mild hyperbaric
oxygen can reverse age-related decline in the oxidative capacity of skeletal
muscles [182]. Since impaired oxidative metabolism is associated with muscle
atrophy with aging, researchers explored the effects of mild hyperbaric oxygen
on muscle loss in hindlimb unloading rats. As a result, a combination of
preconditioning and postconditioning with mild hyperbaric oxygen reversed
atrophy and decreased oxidative capacity of the soleus muscle [183]. Later, the
same research team found that exposure to mild hyperbaric oxygen during
unloading partially inhibited unloading-induced decrease in soleus muscle weight
and type shift from type I to type IIA fibers [184]. Given the interactions
between bone and muscle health [185], researchers next explored the effects of
mild hyperbaric oxygen on bone loss. As a result, mild hyperbaric oxygen
partially protected from osteoporosis in hindlimb unloading rats by inhibiting
the increase of osteoclasts and enhancing bone formation [186]. In conclusion,
mild hyperbaric oxygen can prevent from bone and muscle loss induced by
unloading in rats. Thus, one can speculate that hyperbaric oxygen may be
beneficial in preventing degenerative changes in the musculoskeletal system
during aging. Yet much uncertainty remains, given the single source of data and
current lack of direct clinical evidence. More research is needed to further
confirm the significance of mild hyperbaric oxygen for the musculoskeletal
system in different animal models of aging, and ultimately, in the elderly.

In addition to disuse osteoporosis simulated by unloading, a more common type of
osteoporosis in the elderly arises from aging-related dyshomeostasis of bone
metabolism. Interestingly, previous studies on complete spinal transection have
demonstrated beneficial effects of HBOT on bone metabolism, which in turn lead
to increased bone hardness and flexibility [187,188]. These results have helped
establish the role for HBOT in maintaining bone homeostasis. Better yet, it was
revealed in a recent study that HBOT not only restored bone structure/strength
in aged non-obese rats, but it ameliorated bone dyshomeostasis in aged rats with
obesity [189]. This study provides direct evidence that HBOT can be considered
as a potential intervention in age-related bone pathology to reduce the risk of
osteoporosis and fractures.


4.5. CARDIOPULMONARY FUNCTION IMPROVEMENT

Aging of the heart and lung is accompanied by declining functions and increasing
vulnerability to diseases. Considering that cardiovascular and pulmonary
dysfunction are closely connected during aging [190], we here set out to review
the effects of HBOT on aging of these two systems in parallel.

Both animal and human studies have demonstrated the positive effects of HBOT on
the aging heart. The myocardium of elderly diabetic patients is particularly
vulnerable to the adverse effects of local and systemic factors caused by
diabetes. In pre-diabetic rats after D-gal-induced aging, HBOT ameliorated the
aggravation of cardiac dysfunctions [98], consistent with a previous clinical
trial involving elderly diabetic patients, in which HBOT resulted in improved
myocardial diastolic function [191]. Researchers also examined the effects of
HBOT on myocardial function during normal aging. It was found that HBOT restored
cardiac senescence marker expression and cardiac function parameters in
D-gal-induced aging rats, even to the same level of the vehicle group [98]. HBOT
used under different protocols yields inconsistent results in elderly subjects.
In a clinical study of asymptomatic elderly, HBOT, utilized in a repeated 60
daily sessions protocol at 2 ATA, improved left ventricular and right
ventricular systolic function, and resulted in better cardiac performance, while
no significant changes were observed in diastolic parameters [192]. In contrast,
a slight improvement in diastolic function in the elderly was previously
observed after a single exposure to hyperbaric oxygen while the EF result
reflecting cardiac systolic function showed a negative trend [193]. Despite the
controversy, these results indicate that HBOT, when used in an appropriate
manner, can reverse age-related deterioration of myocardial function. In terms
of pulmonary function, there were concerns about the potential pulmonary oxygen
toxicity of HBOT given the particularity of the therapy. However, a prospective
cohort study revealed that HBOT, utilized in a repeated 60 daily sessions
protocol at 2 ATA, resulted in a modest though statistically significant
improvement in PEF and FVC in subjects with a mean age of 60 years without
chronic lung diseases [194]. Yet, using two different administration protocols,
we were unable to show a positive role of HBOT on pulmonary function [195,196].
The reason for such a discrepancy mainly lies in the HBOT protocols, in which a
prolonged period with lower oxygen pressure is critical. Taken together,
appropriate use of HBOT can resist the degenerative changes of cardiopulmonary
function in the elderly.


5. LIMITATIONS AND FUTURE DIRECTIONS

The benefits of HBOT for healthy aging in both mechanistic and therapeutic
aspects are comprehensively summarized in this review. However, a key issue
remains for existing HBOT research. First of all, HBOT protocols vary widely,
making it difficult to compare and integrate different results. Moreover,
updates on published clinical protocols are warranted so as to accommodate the
general aging populations rather than currently approved indications. Therefore,
a generally applicable HBOT protocol needs to be defined in the subsequent step.

In recent years, HBOT has been used for various new medical conditions with
protocols based on lower oxygen pressure (2 ATA or less) and more daily sessions
(40–60 sessions) [194]. One specific emerging protocol, which utilizes repeated
intermittent hyperbaric exposures, can lead to a series of changes in the aging
populations including transcriptome changes [21], telomere elongation [42],
cognitive enhancement [140], skin rejuvenation [27], and pulmonary function
parameters improvement [194]. The protocol includes 60 daily HBOT sessions of
100% oxygen at 2 ATA for 90 min with intermittent air breaks. Through a
mechanism previously referred to as the hyperoxic-hypoxic paradox, it induces
physiological effects that classically occur in hypoxia state, excluding an
increase in mitochondrial metabolism by activation of SIRT1 [19,85]. These
findings will lay a solid foundation for further research. Another protocol, a
modified version of HBOT called mild hyperbaric oxygen, provides appropriately
high atmospheric pressure and 35–40% oxygen [197]. Although not within the usual
definition of HBOT, this therapy has been shown to reverse degenerative changes
in skin [154,159], bone [186], muscle [183,184] and metabolism [169] in
experimental animals, primarily by promoting oxidative metabolism [197]. Despite
its great potential demonstrated in preclinical studies, there is still a lack
of supporting data from clinical trials regarding this modified version of
therapy. Investigators need to further determine not only the efficacy and
sustainability of existing protocols, but also the dose-response curves related
to oxygen pressure, exposure time, frequency of intervals and number of sessions
in order to optimize treatment conditions. Also, the optimal age range for HBOT
to yield significant protective effects against aging needs to be described.

Concerns about the adverse effects of HBOT remain, possibly due to the exposure
to a special atmospheric environment. Indeed, HBOT cannot be considered an
entirely benign intervention because of the risk of some mild complications
during HBOT, including claustrophobia, barotrauma and visual effects [3,198].
Fortunately, the vast majority of subjects can recover spontaneously from common
complications and serious complications are fairly exceptional, suggesting that
the current procedure is relatively safe [198]. Despite the guaranteed safety,
the acceptable rate of side effects may be even lower when targeting healthy
aging populations rather than patients with specific pathologies. In determining
an applicable protocol of HBOT for healthy aging, the potential benefits must be
carefully weighed against the corresponding risks, and the cost if necessary. To
put it another way, HBOT may be absolutely or relatively contraindicated in some
cases. In addition to the commonly considered contraindications such as
pneumothorax, special attention must be paid to some chronic conditions that
frequently occur in the aging populations. For example, it is demonstrated in a
retrospective study that standard HBOT protocols lead to an absolute rise in
arterial blood pressure (ABP), especially in a hypertensive subgroup [199].
Since a higher baseline ABP is commonly observed in the elderly, appropriate
pre-session ABP levels should be described as thresholds for strict ABP
monitoring during HBOT. In a nutshell, for clinical application in healthy older
adults, technically safer HBOT protocols with more stringent guidelines are
required.

To conclude, previous findings on HBOT have provided valid and sufficient
information on its protective effects against aging. With many remaining
questions beginning to be answered and protocols to be optimized, there are
important discoveries yet to come. Obviously, HBOT has significant and
beneficial implications for aging and age-related conditions, with great
potential for clinical applications to be explored in the future.


AUTHOR CONTRIBUTIONS

QL provided direction and guidance throughout the preparation of the manuscript.
QF performed the literature search and wrote the original manuscript. YS
provided constructive suggestions and made significant revisions to the
manuscript. RD helped revise the manuscript. All authors read and approved the
final manuscript.


DECLARATION OF COMPETING INTEREST

The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported
in this paper.


ACKNOWLEDGMENTS

This work is financially supported by grants from the Innovative Research Team
of High-level Local Universities in Shanghai (SHSMU-ZDCX20210400) and Shanghai
Municipal Key Clinical Specialty (shslczdzk00901) to QL, and National Natural
Science Foundation of China (NSFC) (31871380, 82130045) to YS.


ABBREVIATIONS



HBOT

hyperbaric oxygen therapy

ATA

atmosphere absolute

ROS

reactive oxygen species

SASP

senescence-associated secretory phenotype

HIF-1

hypoxia-inducible factor-1

RNS

reactive nitrogen species

VEGF

vascular endothelial growth factor

EPCs

endothelial progenitor cells

Nrf2

nuclear factor E2-related factor 2

SIRT1

sirtuin1

SA-β-gal

senescence-associated β-galactosidase

D-gal

d-galactose

MMPs

matrix metalloproteinases

SPC

stem/progenitor cell

MSCs

mesenchymal stem cells

CBF

cerebral blood flow

AD

Alzheimer's disease

VD

vascular dementia

UV

ultraviolet

DKD

diabetic kidney disease

ABP

arterial blood pressure



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