Hyperbaric

Redox Biology 53 (2022) 102352
Contents lists available at ScienceDirect
Redox Biology
journal homepage: www.elsevier.com/locate/redox
Hyperbaric oxygen therapy for healthy aging: From mechanisms

to therapeutics
Qiaoyu Fu a, Ran Duan a, Yu Sun b, c, d, **, Qingfeng Li a, *
a
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai,
200011, China
b
Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of
Sciences, Shanghai, 200031, China
c
School of Pharmacology, Institute of Aging Medicine, Binzhou Medical University, Yantai, 264003, China
d
Department of Medicine and VAPSHCS, University of Washington, Seattle, WA, 98195, USA
A R T I C L E I N F O A B S T R A C T
Keywords: Hyperbaric oxygen therapy (HBOT), a technique through which 100% oxygen is provided at a pressure higher
Hyperbaric oxygen therapy than 1 atm absolute (ATA), has become a well-established treatment modality for multiple conditions. The
Aging intervention noninvasive nature, favorable safety profile, and common clinical application of HBOT make it a competitive
Age-related disease
candidate for several new indications, one of them being aging and age-related diseases. In fact, despite the
Oxidative stress
conventional wisdom that excessive oxygen accelerates aging, appropriate HBOT protocols without exceeding
Cellular senescence
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 bio
logical mechanisms and therapeutic implications of HBOT in promoting healthy aging and shed light on pro
spective 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 con
ventional wisdom to scientific findings of translational value.
1. Introduction are, however, a few flies in the ointment (Fig. 1). First, some of the
known therapies, such as young plasma transfusion and stem cell
Aging is characterized by a progressive loss of physiological func grafting, involve a certain degree of invasiveness. Second, despite
tions over time. Not only does aging substantially affect the quality of adequate safety, lifestyle changes alone, such as physical exercise and
life, but it also represents a major risk factor for a number of age-related intermittent fasting, may not be sufficient to ensure definitive efficacy.
diseases. Effective approaches are required to sustain better health in old Third, senotherapeutics, as another modality of noninvasive strategy,
age by slowing down the natural aging process and preventing age- are not yet fully understood in humans and still in their infancy before
related conditions. At present, there are limited options to interfere routine clinical practice, mainly due to the complex, time-consuming
with the aging process, such as stem cell therapy, young plasma trans and expensive procedure of pharmacological development. Therefore,
fusion, physical exercise, intermittent fasting and senotherapeutics [1]. while effectively advancing existing strategies, researchers are also in
These mainstream strategies have inspired great interest in the scientific search of novel strategies to achieve healthy aging that are noninvasive,
community and shown considerable promise in combating aging. There sufficiently effective, and easy to use, among which hyperbaric oxygen
* Corresponding author. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine,
639 Zhizaoju Road, Shanghai, 200011, China.
** Corresponding author. Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
E-mail addresses: dr_fuqiaoyu@163.com (Q. Fu), tracydr@126.com (R. Duan), sunyu@sibs.ac.cn (Y. Sun), dr.liqingfeng@shsmu.edu.cn (Q. Li).
https://doi.org/10.1016/j.redox.2022.102352
Received 22 April 2022; Received in revised form 17 May 2022; Accepted 23 May 2022
Available online 27 May 2022
2213-2317/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Q. Fu et al. Redox Biology 53 (2022) 102352
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) produc
tion, mitochondrial dysfunction and replicative senescence [8–10].
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 pro
Fig. 1. Potential strategies against aging and their deficiencies. Strategies
nounced after repeated exposures, which is discussed in detail in Section
under development to intervene aging include stem cell therapy, young plasma
transfusion, physical exercise, intermittent fasting and senotherapeutics. 3.3. In fact, it has been already reported that systemic levels of oxidative
Despite the great promise of these mainstream strategies, there are three de stress are largely unaltered in healthy young volunteers after multiple
ficiencies among them. (1) Stem cell transplantation and young plasma trans HBOT sessions, with signs of depletion of ROS generation capacity [16].
fusion involve a certain degree of invasiveness. (2) Physical exercise and Likewise, a recent study of HBOT in middle-aged males reported
intermittent fasting alone may not be sufficient enough to ensure definitive attenuation of oxidative stress, as reflected by circulating biomarkers
efficacy. (3) The efficacy of senotherapeutics is not yet fully understood in [17]. These encouraging findings help alleviate concerns that HBOT
humans and the development pipelines are complex, time-consuming results in oxidative damage. More importantly, fluctuations in oxygen
and expensive. concentration levels are perceived by tissues as a hypoxia trigger,
therapy (HBOT) is a competitive candidate.

HBOT is a noninvasive technique to allow 100% oxygen supplied at a
pressure greater than 1 atm absolute (ATA). The treatment was origi
nally 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 ef
fects 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 Fig. 2. The biological consequences of aging with respect to oxygen levels. In
aging process, as well as its potential therapeutic implications supported terms of aging, the truth is not a duality when it comes to the trade-off between
by pre-clinical and small-scale clinical studies. 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
2. The oxygen paradox in aging reduced longevity. To the contrary, modest modulation of oxygen levels (either
increases or decreases in oxygen levels) can enhance the antioxidant defenses
There is a paradoxical relationship between oxygen and aging. and slow the aging process. These facts suggest both an alert threshold in
Despite the indispensable role that oxygen plays in tissue homeostasis hypoxia and a toxicity threshold in hyperoxia in the biological consequences of
and organismal survival, oxygen is considered a key driver of the aging aging with respect to oxygen levels.
2
allowing HBOT over several cycles to stimulate cellular protection this provides clinicians with a wide array of therapeutic targets for aging
characterized by hypoxia-inducible factor-1 (HIF-1) activation without and age-related diseases. At the same time, there is growing evidence for
additional detrimental effects of hypoxia [18,19]. We will discuss this the benefits of HBOT in tissue homeostasis and regeneration. The fact
problem further in Section 3.1 and Section 3.3. that the therapeutic targets of HBOT overlap considerably with those of
The contradictory roles of oxygen in aging can be attributed to the aging and age-related diseases is beginning to gain attention. In a recent
phenomenon of “Hormesis”. The term describes the fact that treatment prospective trial, HBOT was found to induce transcriptome changes in
with sub-toxic and non-damaging doses of a certain toxicant can actually whole-blood samples from healthy aging subjects, with 1342 genes
induce adaptations that prevent subsequent damage by the same agent upregulated and 570 genes downregulated [21]. Changes in these age
[14]. The oxygen in HBOT may represent such a sub-toxic substance. genetic signatures in vivo suggest remarkable effects of HBOT on the
Doubtless, there exists a “toxicity threshold” in terms of quantity and elderly, at least at the molecular level. In this section, we aim to place
duration [20], beyond which oxygen administration will speed up the HBOT in the context of various aging theories and summarize possible
aging process instead. The thresholds vary by species, age and tissue, mechanisms by which HBOT promotes healthy aging (Fig. 3).
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 3.1. Angiogenesis enhancement
plays an active role against aging under appropriate protocols of HBOT
without exceeding the toxicity threshold. It forms the basis for our Impaired vascular homeostasis and angiogenesis, one of the hall
subsequent discussion about the role of HBOT in the field of aging and marks of aging, leads to reduced capillary density throughout the body,
geriatric research. which in turn contributes to fading physical functions in the elderly [22,
23]. The corollary to this “angiogenesis hypothesis of aging” recom
3. The mechanisms by which HBOT intervenes aging mends pro-angiogenesis therapy for symptoms and signs of aging [23].
Meanwhile, oxygen is essential for angiogenesis. Exposure to oxygen
Substantial progress has been made in comprehending the molecular increases angiogenesis in a dose-dependent manner [24]. And the
mechanisms of the aging process over the past few decades. Obviously, stimulus for angiogenesis seems not to be the increased oxygen avail
ability by itself, but to be most related to the pressure at which it is
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
delivered [25]. Thus, both the hyperoxia and pressure components of neutrophil-like cells is observed after a single 90 min exposure to hy
HBOT play an indispensable role in promoting angiogenesis. To date, perbaric oxygen, as evidenced by promoted caspase 3/7 activity and
numerous studies have reported the pro-angiogenesis effects of HBOT in morphological changes associated with apoptosis [55]. In another study,
different tissues with compromised blood perfusion such as skin neutrophils from severely injured patients or healthy volunteers
[26–29], brain [30–32], penile [33], bone [34], and even tumor [35, respectively showed no significant reduction in apoptosis but a decline
36]. These results firmly establish the pro-angiogenesis effects of HBOT, in ROS production, MAPKs activation and NETs release after exposure to
implying its possible advantages in preventing age-related microcircu hyperbaric oxygen [56]. Despite the contradiction, both in vitro studies
lation impairments. suggest a role for HBOT in limiting neutrophil-mediated systemic
The mechanisms of HBOT impacting angiogenesis have been inflammation. This has been confirmed by in vivo experiments using
explored in various animal models. There is an age-related signaling different animal models, in which HBOT reduces neutrophil recruitment
decline in HIF-1, contributing to the defective neovascularization with and activation [57,58]. Apart from its effects on neutrophils, hyperbaric
natural aging [37]. Interestingly, it has been widely reported in the oxygen can induce the apoptosis of lymphocytes as well via a
literature that HBOT induces an increase in HIF-1 [38,39]. HIF-1, con mitochondrion-associated mechanism, demonstrated by caspase-9 acti
sisting of HIF-1α and HIF-1β subunits, is an essential mediator of oxygen vation and loss of mitochondrial membrane potential [59,60]. Besides,
homeostasis, whose biological activity is determined by the expression HBOT can reduce inflammation by regulation of iNOS activity/ex
of HIF-1α subunit [40]. Hypoxia is the main regulator of its function and pression and nitrite/nitrate production in lymphocytes, as observed in
activity. Aside from that, there are many other regulatory factors, among T1DM patients [61]. These results illustrate that HBOT suppresses
which are free radicals including ROS and reactive nitrogen species lymphocyte-mediated inflammatory responses both quantitatively and
(RNS) [41]. Correspondingly, there are generally two approaches to qualitatively. For T lymphocytes, a single exposure to hyperbaric oxygen
modulating HIF-1α by HBOT. For one thing, a unique protocol of can result in a transient reduction in the CD4:CD8 ratio in blood from
repeated intermittent hyperoxia exposures, with a 5-min air break every healthy volunteers [62], reinforcing the role of HBOT in reversing
20 min, can induce some cellular mechanisms usually induced during immunosenescence as an augment in the CD4:CD8 ratio with aging was
hypoxia, including the release of HIFs and increase in their stability and previously reported in human peripheral blood [63,64]. The brain is
activity [27,42]. This is because the return to normoxia following a known as an immune-privileged organ, in which astrocytes act in con
hyperoxia exposure results in fluctuations in the dissolved oxygen, cert with microglia in neuroinflammation during normal aging, leading
which are interpreted by tissues as a lack of oxygen though hypoxia does to cognitive impairment [65]. HBOT can attenuate neuroinflammatory
not actually occur, namely the so-called “hyperoxic-hypoxic paradox” processes by reducing astrocytes and microglia activation in different
[19]. The same applies to the general HBOT protocols since intermittent animal models including aging [66], Alzheimer’s Disease (AD) [67] and
fluctuations in oxygen occur between daily treatments [43]. For brain injury [68]. These results confirm that HBOT’s effects on inflam
another, it has been widely acknowledged that HBOT leads to elevated matory cells are not limited to those in the blood circulation.
partial pressure of oxygen in blood and tissues, which in turn increases At the molecular level, HBOT can target the inflammatory process
the production of ROS [39,43,44] and RNS [44,45]. The transiently through its extensive effects on the expression of cytokines and other
increased ROS and RNS serve as signaling molecules to stabilize HIF-1 in mediators. Various pro-inflammatory cytokines and inflammatory me
its active form [44]. Following the stabilization and activation of HIF-1, diators are reduced in the peripheral blood following HBOT, including
HIF-dependent vascular endothelial growth factor (VEGF) stimulation IL-1β, IL-2, IL-6, TNF-α, IFN-γ, PGE2, COX-2 [60,69–72]. The same goes
contributes to blood vessel formation directly [40,46,47]. In addition to for the levels of inflammatory markers in different tissues. Meanwhile,
the commonly observed increase in VEGF after HBOT in the literature HBOT can lead to increases in some anti-inflammatory cytokines,
[26,38,48,49], several reports have revealed other angiogenic markers including IL-1Ra, IL-4 and IL-10 [48,67,72–74]. Among them the most
induced by HBOT, such as EGF, PDGF, CXCL10, IL- 1α, FGF-2 and SDF-1 frequently reported is IL-10, the major mediator of protective effects of
[26,48]. These angiogenic factors, especially the most prominent HBOT against sepsis [75] and traumatic brain injury [76]. There are
proangiogenic factor VEGF, work together to activate vascular cells to conflicting results pertaining to acute phase proteins [77], with most
promote angiogenesis and arteriogenesis [50]. Among them, reports showing a decrease in CRP while a few showing stimulation of
HIF-1-regulated VEGF and SDF-1 can also reach the circulation and G-CSF and inhibition of IGF-1. As an overall effect, it has been reported
stimulate bone marrow-derived endothelial progenitor cells (EPCs) that HBOT can exert protective effects against multi-organ damage
mobilization and recruitment, thus promoting angiogenesis and vascu following generalized inflammation [78]. Mechanisms include that hy
logenesis [50,51], which has been demonstrated in human subjects perbaric oxygen can interfere with the TLR/NF-κB pathway, accounting
receiving HBOT [50,52,53]. Another nuclear factor E2-related factor 2 for a downregulation of pro-inflammatory cytokine release [78]. Given
(Nrf2) signaling pathway induced by HBOT has also been shown to that the aging process is accompanied by the activation of multiple in
stimulate angiogenesis, possibly through its interaction with VEGF and flammatory pathways throughout the body, the results suggest that
other angiogenic factors [48]. HBOT may protect various tissues from chronic inflammatory damage
during aging in a similar manner.
3.2. Immunomodulatory properties Collectively, HBOT appears to exert anti-inflammatory effects in a
variety of both physiological and pathological conditions. So far, re
Immune dysregulation and activation of inflammatory pathways searchers have preliminarily observed benefits of HBOT in slowing
have been postulated to be essential contributors to tissue dysfunction in down tissue aging by attenuating inflammation, while more compre
the course of aging [54]. The chronic, sterile, low-grade inflammatory hensive research is expected to clarify the systemic effects of HBOT on
state during aging, also known as inflammaging, plays a vital role in the age-related inflammatory state.
pathogenesis of age-related diseases. In recent years, interventions tar
geting inflammatory pathways have shown great potential in the reju 3.3. Elevation of antioxidant activity
venation of different tissues, thereby preventing age-related tissue
dysfunction [54]. Coincidentally, HBOT has shown its immunomodu Oxidative stress is induced when ROS production exceeds antioxi
latory properties from the beginning of its use, suggesting its benefits in dant capacity. The oxidative stress theory of aging takes it as a major
ameliorating age-related immune dysregulation. mechanism responsible for age-related functional losses and longevity
At the cellular level, HBOT can exert immunomodulatory effects on a limitation. At the same time, the decrease in mitochondrial efficiency
variety of inflammatory cell types. Neutrophil apoptosis plays a crucial plays a significant role in oxidative stress induced with aging [79], since
part in the resolution of inflammation, while enhanced apoptosis of mitochondrion is a primary site for ROS production in the cell. We have
4
summarily described the biological consequences of excessive oxygen on in HBOT remains to be further elucidated. Synergistically with
oxidative stress and antioxidant defense in Section 2. In this section, we SIRT1-mediated beneficial effects, there is a distinct increase in scav
discuss in detail the role of HBOT on oxidative stress balance, as well as enging activity induced by ROS production following repeated expo
its effect on mitochondrial function (Fig. 4). We will pay particular sures, while the elimination half-life of scavengers is much longer than
attention to the antioxidant potential of HBOT when applied appropri that of ROS [19]. The biphasic response has been confirmed by a study
ately as an alternative theoretical mechanism. revealing that HBOT-induced DNA damage can only be detected
Under different protocols and pathological conditions, studies over immediately after the first treatment but not after subsequent treatments
the past few decades on the effects of HBOT on mitochondrial properties under the same conditions, suggesting that repeated exposures can
and oxidative stress balance have yielded mixed results [43]. On the one result in an increased antioxidant protection but not an accumulation of
hand, HBOT is thought to cause excessive ROS production and induce oxidative damage [87]. Taken together, contrary to short-term pro
oxidative stress, implying adverse effects while being therapeutic under tocols, long-term HBOT or repeated intermittent hyperbaric oxygen
certain circumstances [77,80]. This is accompanied by a reduction in exposures can enhance antioxidant defenses via adaptive mechanisms.
mitochondrial function [81]. On the other hand, HBOT has been found Apart from that, exposure pressure and frequency have been proposed as
to improve mitochondria activity as well as increase free radical scav important factors to consider when investigating antioxidant responses
engers, thereby providing effective antioxidant defense [13,17,43,48, induced by HBOT [88]. The contributions of variables other than the
49]. Despite the multifactorial process, the contradiction has mainly number of sessions warrant further investigation.
been attributed to the number of sessions [43]. Generally, a single Mechanistically, HBOT activates a series of transcription factors and
exposure to hyperbaric oxygen or short-term HBOT may create oxidative gene expression to increase endogenous antioxidant enzymes [13]. Nrf2,
stress. Via mitochondrion-dominated mechanisms, HBOT leads to a redox sensor, represents the master regulator of cellular defenses
elevated ROS production. Although there is an increase in scavenger against oxidative stress [89]. The age-dependent decline in antioxidant
production as an adaptive response to ROS accumulation, the compen enzyme responses is supposed to result from decreased expression of
sation is inadequate and gradual after limited exposures [19]. In par Nrf2 and its target genes [90]. Accumulating data suggest that HBOT
allel, mitochondrial respiration is reduced in order to counteract induces antioxidant responses by upregulating Nrf2 and its downstream
additional ROS production [81]. Sirtuin1 (SIRT1) is considered a major targets, such as HO-1, NQO-1, CAT, GPx, SOD and GCLC [48,91–93].
metabolic stimulator of mitochondrial biogenesis and part of a cellular Reversal of age-related decline in Nrf2 signaling by HBOT makes it a
defense mechanism against oxidative stress [82,83]. Its reduction with viable therapeutic option for aging of the antioxidase system. Besides
aging contributes to age-related disorders. After repeated intermittent increased expression of antioxidant enzymes, decreased levels of enzy
hyperoxia exposures or long-term HBOT, SIRT1 is significantly activated matic pro-oxidants, such as iNOS and gp91-phox, have also been
through increased NAD + levels from the hyperoxic state during HBOT observed in two separate studies [74,94]. In conclusion, HBOT induces
[84,85], improving mitochondrial biogenesis via acetylation of PGC-1α an increase in antioxidant enzymes and a decrease in pro-oxidant en
and inducing antioxidant responses via deacetylation of FOXO3a [19]. zymes through a negative feedback, thereby enhancing the antioxidant
Notably, HIF-1, which is also activated after HBOT as described in defenses.
Section 3.1, antagonizes the promoting effect of SIRT1 on mitochondrial
biogenesis [86]. The crosstalk between the HIF-1α and SIRT1 pathways
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.
5
3.4. Suppression of cellular senescence 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
The accumulation of senescent cells in various tissues is regarded as a telomere length in various tissues and thus a useful biomarker of human
significant contributor to aging as well as age-related diseases. Mean aging [107]. For divers exposed to intense hyperbaric oxygen, a previous
while, cellular senescence can be characterized by multiple features, study showed telomere elongation in leukocytes over a 12-month in
which have emerged as potentially effective targets for therapeutic terval [108]. Similarly, a recent clinical trial in healthy aging pop
exploitation [95]. Here we review the effects of HBOT on cellular ulations has revealed that HBOT can target cellular senescence in
senescence from multiple perspectives. isolated leukocytes in terms of telomere shortening and accumulation of
So far, no single marker with absolute specificity for senescent cells senescent cells [42]. Unfortunately, neither telomerase activity nor the
has been established [96]. Two classic tools to identify senescent cells in expression of CD57, the most reliable surface marker for T cell senes
vivo include senescence-associated beta galactosidase (SA-β-gal) and cence, was evaluated in this study, complicating the interpretation of the
cyclin-dependent kinase inhibitors including p16 and p21 [97]. results. In addition to the effect of HBOT on circulating immune cells,
Intriguingly, in two independent reports, HBOT respectively showed its the restoration of telomere length was also observed in the hippocampus
ability to attenuate aging markers in the hippocampus of D-galactose after HBOT in aging and obese rats with shortened telomeres [66]. By
(D-gal)-induced aging mice, as demonstrated by decreased number of and large, HBOT makes a difference in inhibiting telomere shortening,
SA-β-gal positive cells [66] and reduced expression of key components of but it remains to be clarified how hyperbaric oxygen targets telomeres
the senescence program, such as p16, p21 and p53 [71]. It has also been and how its response relates to different conditions.
shown that HBOT can reduce the number of SA-β-gal positive cells in It appears to be an attractive rationale to blunt the pro-aging effects
cardiomyocytes in aging pre-diabetic rats [98]. In another study, re of senescent cells with HBOT. At the present stage, the study on un
searchers evaluated cellular senescence by lipofuscin, another estab derstanding the role of HBOT in senescent cells is still in its infancy, but
lished biomarker, and found senescent cells cleared from skin after with rapid progress. Future work is essential and expected to examine
HBOT [27]. However, new indicators for senescence such as LINE1 have suitable biomarkers of cellular senescence. Given the diversity of se
been recently developed [99], which are absent from existing HBOT nescent cells of different origins, it is necessary to evaluate the effects of
studies. Besides, a multi-parametric strategy for identification of se HBOT on cellular senescence in various systems in vivo.
nescent cells is currently being advocated [96]. For example, the use of
SA-β-gal assay in combination with nuclear HMGB1 staining allows a 3.5. Stem cell regulation
more accurate evaluation of senescence than SA-β-gal staining alone
[100]. Therefore, the pleiotropic phenotypes of senescent cells have not Stem cell can promote tissue regeneration not only by replacing dead
been considered in the existing literature, which is clearly a limitation. cells with new ones, but also by secreting cytokines and growth factors,
In tissues, senescent cells are heterogeneous but share a number of making them prime targets in aging and regenerative medicine. Based
common features, among which the most widely recognized are the on that, an attractive theory of aging holds that the loss of stem cell
permanent cell cycle arrest and a bioactive secretome, namely the SASP number and activity over time drives organismal aging [109]. Interest
[97]. Critical components of pathways involved in senescence-mediated ingly, studies in various tissues and diseases have established stem cells
cell cycle arrest include p16, p21 and p53 [101], which, as noted above, as key players in the regenerative effects of HBOT. It can be inferred that
tend to decrease after HBOT [71], reflecting the potential of HBOT to regulating stem cell biology to slow aging by HBOT may be feasible in at
resume cell cycle progression in senescent cells. In prostate cancer cells, least three aspects.
a single exposure to hyperbaric oxygen causes senescent cells to enter First, HBOT can stimulate stem/progenitor cell (SPC) mobilization
cell cycle [102]. Likewise, exposure to hyperbaric oxygen can prevent and recruitment from bone marrow. As described in Section 3.1, HBOT
cell cycle arrest in malignant glioma cells [36]. Nevertheless, the current mobilizes SPCs by stimulating NOS, increasing its circulating population
results are insufficient to illustrate the general effects of HBOT on se and intracellular regulatory protein content [52,110]. The mobilized
nescent cells, as cancer cells are more likely to overcome the SPCs have been found to be engaged in wound healing [110,111] and
senescence-associated cell cycle arrest. Senescent cells secrete the SASP, cognition enhancement [112,113]. Second, HBOT can cause changes
which usually consists of pro-inflammatory cytokines and chemokines, intrinsic to SPCs, including the promotion of stem cell proliferation and
angiogenic factors, growth factors, and matrix metalloproteinases differentiation, as well as the regulation of protein secretion. In vivo,
(MMPs) [96,97]. The downregulation of a variety of factors involved in HBOT has been reported to stimulate proliferation of neural stem cell
the SASP after HBOT has been described in Section 3.1 and Section 3.2. [114,115] and intestinal stem cell [116], growth and differentiation of
Moreover, the declined expression of MMPs after HBOT has also been vasculogenic stem cell [117], and activation of colonic stem cells [118].
well documented [94,103,104]. Therefore, there is sufficient evidence In vitro, HBOT can promote proliferation and differentiation of
to support the role of HBOT in blocking SASP. Since development of the adipose-derived stem cells [119], as well as osteogenic and vasculogenic
SASP can partially explain the deleterious, pro-aging effects of senescent differentiation of mesenchymal stem cells (MSCs) [120,121]. The
cells [96], the downregulation of SASP expression by HBOT may alle secretion profile of proteins is also modulated by HBOT in MSCs, with
viate the pro-aging effects of senescent cells to a certain extent, or more some upregulated proteins being neuroprotective and others involved in
optimally, reflect the result of senescent cell clearance. In general, cellular mechanisms against oxidative stress [122]. While the above two
specific therapies to target senescent cells are referred to as senother mechanisms potentially ensure the efficacy of HBOT alone by stimu
apeutics, consisting of senomorphics and senolytics [105]. The former lating inherent stem cells, the third mechanism we summarize here is
indirectly impedes the appearance of senescence phenomenon through that combining HBOT with stem cell transplantation can enhance the
blocking the SASP, while the latter selectively clears senescent cells therapeutic value of stem cells. Compared with monotherapy, a com
[100,106]. Some of them have been shown to markedly intervene with bined treatment of stem cell transplantation and HBOT has shown better
the aging process in animal models. In practice, however, only a few therapeutic effects on cardiac regeneration [123], neurological function
senolytics have entered early-stage clinical trials, while senomorphics recovery [124], and metabolic control [125]. Considering the great
have yet to enter clinical trials with greater potential risks [105]. It promise of stem cell transplantation in aging or geriatric medicine, it is
seems that the role of HBOT coincides with theirs in intervening in speculated that HBOT can be used as an adjunct therapy to improve
cellular senescence. To some extent, this raises the possibility that HBOT survival and function of the transplanted stem cells. Despite the
can be utilized as an available alternative to senotherapeutics, or as an encouraging findings, research gaps in the effects of HBOT on stem cell
adjunct therapy. properties in the elderly are worth filling through continued studies in
One of the major pro-senescence stimuli is telomere shortening [97], the future.
6
4. Therapeutic implications of HBOT in aging intervention measured cognitive domains yielded neutral results, consistent with
previous studies on single oxygen exposure that not all cognitive do
Supported by the multiple mechanisms described above, the past mains can be improved by oxygen administration [127,134].
decade has seen an explosion of interest in the rejuvenation potential of Back in 1970s, researchers first investigated the effects of HBOT on
HBOT that goes far beyond its traditional use in medicine. We hereby set cognitive impairment in the elderly, with conflicting results though
out to review the potential therapeutic implications of HBOT in aging [135,136]. Only in recent years have researchers begun to refocus on the
intervention from the existing literature (Fig. 5). cognitive protective effects of HBOT in the context of normal aging. It is
widely acknowledged that D-gal-induced model can mimic natural
4.1. Cognitive improvement aging associated with neurodegeneration [137]. In D-gal-induced pre
clinical aging model [66,71,138] or combined model of D-gal-induced
As the largest consumer of oxygen, the brain comprises only 2% of aging and obesity [66], HBOT has shown the ability to prevent cognitive
the body’s weight and yet utilizes 20% of the total oxygen and consumes impairments and attenuate hippocampal pathologies. The demonstrated
25% of the total glucose [126]. Considering the importance of oxygen to mechanisms include improvement of cholinergic and anti-apoptotic
the brain, researchers have displayed great interest in applying HBOT to functions [138], inhibition of oxidative damage and inflammatory re
neurological disorders. Cognitive decline begins as early as the third sponses [66,71], as well as modulation of age-related gene expression
decade even in the absence of pathologic neurodegeneration, making it [71]. However, despite the convenience of D-gal-induced aging model
a symbol of both healthy and neurodegenerative brain aging [126]. Here compared with naturally aging model, a meta-analysis of D-gal-induced
we review the role of HBOT in cognitive improvement, especially in the brain aging models reported significant heterogeneity between studies
context of normal aging as well as neurodegenerative brain aging. on neurobehavioral and neurochemical outcomes [139], suggesting that
Early studies showed that transient oxygen administration to healthy such results should be interpreted with great caution. Despite the flaw,
young adults, even at normobaric conditions, significantly enhances attempts have been made to apply HBOT to improve cognition in the
cognitive function through increased brain activation, as tested by aging populations. In a randomized controlled trial involving 63 healthy
different cognitive measures including word recall [127], n-back task aging subjects, HBOT, utilized in a repeated 60 daily sessions protocol,
[128], visuospatial task [129], verbal cognitive test [130], etc. Later, was shown to induce cognitive enhancements in clinical aspects
HBOT emerged as a novel approach to temporarily enhance cognitive including attention, information processing speed and executive func
function in healthy adults. It was reported that HBOT could improve tions, likely by an increase in regional cerebral blood flow (CBF) [140].
memory performance in young healthy adults [131]. In another study It’s worth noting that the study excluded transient effects of oxygen, as
including healthy adults aged 22 to 68, HBOT significantly improved all changes were evaluated at 1–2 weeks after the last session. The in
cognitive, motor as well as multitasking performance [132], implying crease in CBF was later confirmed by another study of HBOT in elderly
that HBOT benefits the brain beyond what was previously known. The individuals suffering from significant memory loss [141].
study was further continued by the same team to examine the effects of Over the years, studies investigating the effects of HBOT on various
HBOT on major cognitive domains, with the most pronounced neurological disorders including traumatic brain injury [32], anoxic
enhancement of episodic memory [133]. On the other hand, some other brain damage [142], and stroke [143], have provided satisfactory
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.)
7
neurotherapeutic effects, one of which is enhanced cognitive function. photoaging.

Of particular relevance to the current review, apart from being a direct It is worth noting that strictly speaking, some of the studies
cause of the chronological cognitive decline, aging is also the greatest mentioned above involving hyperbaric exposure with moderate atmo
risk factor for dementia [144], which is characterized by pathological spheric pressure and oxygen concentration [154,159] or simply hyper
and progressive cognitive decline. Among the various types of dementia, oxic exposure [158], are actually beyond the definition of HBOT. Yet
AD is the most prevalent one, followed by vascular dementia (VD) [144, these studies have confirmed the importance of oxygen to revitalize the
145]. To date, mounting evidence has supported the notion that HBOT aging skin. Up to now, the role of HBOT in skin aging has not been fully
should be considered an effective treatment for both AD [67,141,146, understood. More supporting evidence is needed to determine how high
147] and VD [145,148], given the desirable cognitive-improving results oxygen concentration affect the aging skin from every aspect of intrinsic
in animal models and clinical trials. Interestingly, the pathology and and extrinsic aging both clinically and histologically. Given the varying
biochemistry of late-life dementia, especially AD, share some common test conditions in the existing literature, it is also necessary to figure out
features with those of normal aging [149,150]. We also note in the the optimal atmospheric pressure, oxygen concentration and time of
literature that the effects of HBOT in dementia somehow resemble those treatment for maximal skin benefit. However, with the few positive
in normal aging, such as attenuating neuroinflammation [67] and outcomes, the use of HBOT or hyperoxia conditions for skin rejuvenation
increasing CBF [141], which further confirms the benefits of HBOT for has turned out to be promising and effective, at least to a certain extent.
the aging brain, in both physiological and pathological settings.
4.3. Metabolism regulation
4.2. Skin rejuvenation
It has been commonly accepted that aging is associated with a loss of
Unlike other organs of the human body, skin aging is not only metabolic homeostasis and plasticity. Accordingly, greater metabolic
inevitably affected by the intrinsic aging process, as happens in all tis diseases incidence rate estimates have been also observed in the elderly.
sues, but also subject to the unique process of extrinsic aging or pho The main mechanism of HBOT includes the regulation of oxidative stress
toaging, resulting from exposure to environmental agents, particularly balance, which is closely related to the pathogenesis of age-related
ultraviolet (UV) radiation [27,151]. Photoaged skin has several clinical metabolic conditions. Therefore, the effects of HBOT on metabolic pa
and histologic manifestations distinct from those of intrinsic aged skin rameters, especially glucose metabolism, have been extensively
[151]. Here, we review the role of hyperbaric oxygen in skin rejuve addressed in recent years.
nation in terms of intrinsic aging and photoaging respectively. Glucose homeostasis depends on appropriate insulin secretion and
Like any other tissue, the intrinsic physiological aging of the skin is the sensitivity of receptors to insulin, both of which are impaired with
accompanied by the accumulation of senescent cells [151]. Moreover, advancing age [160] In two studies involving animal models of
the dermis of intrinsically aged skin shows degradation of collagen and D-gal-induced aging and combined model of D-gal-induced aging and
elastic fibers [152], as well as diminished blood supply [153]. A recent obesity, HBOT attenuated disturbances of glucose metabolism, mediated
clinical trial demonstrated that repeated intermittent hyperbaric expo by restored insulin sensitivity instead of enhanced insulin secretion [66,
sures had dramatic aging-modulating effects on the skin, illustrated as 98]. In another study, following a reduction in AGEs, the levels of TNF-α
decreased senescent cells, increased elastic fiber length and stability and and IL-6, independent biomarkers predicting the development of insulin
collagen density, and induced angiogenesis [27]. Notably, this study resistance and type 2 diabetes mellitus [161], were decreased signifi
focused on intrinsic aging by taking skin biopsies from a light protected cantly after HBOT in D-gal-induced aging mice [71]. To the best of our
area. The increase in angiogenesis and collagen density was in line with knowledge, however, no clinical trials to date have tapped into the ef
previous reports of HBOT in skin conditions including wound healing fects of HBOT on glucose metabolism in healthy aging populations. In
[26,28] and compromised grafts and flaps [29]. In the epidermis, the existing clinical trials involving healthy individuals of a wide range of
intrinsic physiological aging can be characterized by a generalized ages, HBOT has shown a tendency to lower serum insulin [162], increase
epidermal atrophy [151] mostly due to a decrease in proliferative ac peripheral insulin sensitivity [163] and reduce HbA1C [163], indicating
tivity and turnover rate of epidermal basal cells [152,154]. It is reported that HBOT modulates glucose metabolism by increasing insulin sensi
that exposure to mild hyperbaric oxygen with 36% oxygen reversed the tivity in healthy adults [162]. Meanwhile, no significant reduction in
age-related decline in proliferative activity of epidermal basal cells in blood glucose levels was observed in those studies, implying a low risk of
the skin of aged mice [154]. These results supported the point that the hypoglycemia when HBOT was applied to individuals without diabetes
intrinsically aged skin can be partially revitalized by hyperbaric oxygen, [163,164]. Given the age-related impairments of insulin sensitivity in
whose potentiality has not been sufficiently realized. humans [160], these findings, along with the results from animal models
In contrast to intrinsic aging, photoaging is featured by a thicker of aging, indicate that HBOT may benefit the aging populations in terms
skin, with deep marked wrinkles and irregular pigmentation [155]. of glucose metabolism by attenuating age-related insulin resistance.
Photoaging of the skin is mostly attributable to UV irradiation, partic In addition to the possible positive effects on glucose metabolism
ularly UVA and UVB. UVA (320–400 nm) have a strong penetrating during normal aging, HBOT has shown clinical efficacy in lowering
ability, interacting with both epidermal keratinocytes and dermal fi blood glucose and improving insulin sensitivity in type 2 diabetes mel
broblasts [156]. Pretreatment with HBOT protected skin from litus [164–167], the most common age-related metabolic disorder.
UVA-induced oxidative damage in a mouse model, manifested by re Notably, the majority of participants in these studies received HBOT for
ductions in apoptosis and proliferation of the skin, as well as prevention treatment of diverse conditions including non-healing ulcers and dia
from deleterious structural changes such as creasing and decreased betic foot ulcers, leading to an older age range [165]. It suggests that
elasticity [157]. As a highly energetic component of UV light, UVB these conclusions may be more applicable to the elderly diabetic pop
(280–320 nm) are the major environmental threat to the skin, increasing ulation. Relevant mechanisms by which HBOT improves glucose meta
the risk of long-term damage [156]. A previous study found that expo bolism, as shown in animal models, include enhancements in oxidative
sure to hyperoxia (90% oxygen) immediately after UVB irradiation capacity and GLUT4 expression in skeletal muscle [168,169], as well as
attenuated acute UVB-induced skin angiogenesis and wrinkle formation increases in brown adipose tissue volume and thermogenesis by upre
in adult mice [158]. Moreover, in healthy individuals, it was reported gulating protein levels of UCP1 and PGC− 1α [168,170]. Moreover,
that hyperbaric exposure at 1.25 ATA with 32% oxygen led to both the HBOT has been proven to be beneficial for treating diabetic kidney
fading in melanin pigmentation induced by UVB irradiation and the disease (DKD) in animal studies [171,172] and preliminary clinical trials
decrease in senile spot size [159]. Taken together, high oxygen con [173,174]. Considering the well-established role of HBOT in diabetic
centration has demonstrated surprising potential in treatment of skin foot ulcers, along with the potential benefits of HBOT on blood glucose
8
and DKD, there is a strong case for further research on role of HBOT in the role for HBOT in maintaining bone homeostasis. Better yet, it was
treatment and prevention of the development of diabetes mellitus. revealed in a recent study that HBOT not only restored bone structur
Insulin resistance is often accompanied by central obesity, hyper e/strength in aged non-obese rats, but it ameliorated bone dyshomeo
glycaemia, dyslipidaemia and hypertension, collectively known as a stasis in aged rats with obesity [189]. This study provides direct
pathological condition called metabolic syndrome, which is also com evidence that HBOT can be considered as a potential intervention in
mon in the elderly. In rats with metabolic syndrome, apart from age-related bone pathology to reduce the risk of osteoporosis and
enhanced insulin sensitivity, researchers also observed improvements in fractures.
biochemical parameters of dyslipidemia after HBOT [175,176] or
exposure to mild hyperbaric oxygen [169], consistent with the alter 4.5. Cardiopulmonary function improvement
nations of lipid profiles in diabetic subjects receiving HBOT [166,177].
Interestingly, HBOT also ameliorated obesity by reducing adipocyte Aging of the heart and lung is accompanied by declining functions
hypertrophy in rats with metabolic syndrome [175] and diabetic rats and increasing vulnerability to diseases. Considering that cardiovascular
with obesity [178], and in the former even significantly decreased body and pulmonary dysfunction are closely connected during aging [190],
weight together with abdominal and epididymal fat [175]. However, no we here set out to review the effects of HBOT on aging of these two
effect on lipid profile or body weight was observed in reports of aging or systems in parallel.
aging-obese rats [66,98]. It is unclear whether this contradiction is due Both animal and human studies have demonstrated the positive ef
to the assumption that diabetic rats are more sensitive to the effects of fects of HBOT on the aging heart. The myocardium of elderly diabetic
HBOT on lipid metabolism and obesity, or simply due to the differences patients is particularly vulnerable to the adverse effects of local and
in experimental methods. systemic factors caused by diabetes. In pre-diabetic rats after D-gal-
Collectively, HBOT has shown potential in alleviating impaired in induced aging, HBOT ameliorated the aggravation of cardiac dysfunc
sulin sensitivity in normal aging and age-related metabolic conditions tions [98], consistent with a previous clinical trial involving elderly
including type 2 diabetes mellitus and metabolic syndrome. These diabetic patients, in which HBOT resulted in improved myocardial
findings are going to be the basis for further work on detailed effects of diastolic function [191]. Researchers also examined the effects of HBOT
HBOT on age-related metabolic alternations. on myocardial function during normal aging. It was found that HBOT
restored cardiac senescence marker expression and cardiac function
4.4. Musculoskeletal restoration parameters in D-gal-induced aging rats, even to the same level of the
vehicle group [98]. HBOT used under different protocols yields incon
Musculoskeletal aging, resulting from various age-related changes in sistent results in elderly subjects. In a clinical study of asymptomatic
body composition, inflammation and hormonal imbalance, is closely elderly, HBOT, utilized in a repeated 60 daily sessions protocol at 2 ATA,
correlated with high morbidity and healthcare rates in the elderly. In improved left ventricular and right ventricular systolic function, and
recent years, researchers have demonstrated that mild hyperbaric oxy resulted in better cardiac performance, while no significant changes
gen under 1.25 ATA with 36% oxygen, can be effective against degen were observed in diastolic parameters [192]. In contrast, a slight
erative changes in the musculoskeletal system. The rodent model of improvement in diastolic function in the elderly was previously
hindlimb unloading, which was developed to simulate microgravity observed after a single exposure to hyperbaric oxygen while the EF
conditions, has become a commonly used method for modelling a nat result reflecting cardiac systolic function showed a negative trend [193].
ural decrease in muscle mass defined as sarcopenia [179,180], as well as Despite the controversy, these results indicate that HBOT, when used in
disuse osteoporosis frequently found in the bedridden elderly [181]. an appropriate manner, can reverse age-related deterioration of
Exposure to mild hyperbaric oxygen can reverse age-related decline in myocardial function. In terms of pulmonary function, there were con
the oxidative capacity of skeletal muscles [182]. Since impaired oxida cerns about the potential pulmonary oxygen toxicity of HBOT given the
tive metabolism is associated with muscle atrophy with aging, re particularity of the therapy. However, a prospective cohort study
searchers explored the effects of mild hyperbaric oxygen on muscle loss revealed that HBOT, utilized in a repeated 60 daily sessions protocol at 2
in hindlimb unloading rats. As a result, a combination of precondition ATA, resulted in a modest though statistically significant improvement
ing and postconditioning with mild hyperbaric oxygen reversed atrophy in PEF and FVC in subjects with a mean age of 60 years without chronic
and decreased oxidative capacity of the soleus muscle [183]. Later, the lung diseases [194]. Yet, using two different administration protocols,
same research team found that exposure to mild hyperbaric oxygen we were unable to show a positive role of HBOT on pulmonary function
during unloading partially inhibited unloading-induced decrease in so [195,196]. The reason for such a discrepancy mainly lies in the HBOT
leus muscle weight and type shift from type I to type IIA fibers [184]. protocols, in which a prolonged period with lower oxygen pressure is
Given the interactions between bone and muscle health [185], re critical. Taken together, appropriate use of HBOT can resist the degen
searchers next explored the effects of mild hyperbaric oxygen on bone erative changes of cardiopulmonary function in the elderly.
loss. As a result, mild hyperbaric oxygen partially protected from oste
oporosis in hindlimb unloading rats by inhibiting the increase of oste 5. Limitations and future directions
oclasts and enhancing bone formation [186]. In conclusion, mild
hyperbaric oxygen can prevent from bone and muscle loss induced by The benefits of HBOT for healthy aging in both mechanistic and
unloading in rats. Thus, one can speculate that hyperbaric oxygen may therapeutic aspects are comprehensively summarized in this review.
be beneficial in preventing degenerative changes in the musculoskeletal However, a key issue remains for existing HBOT research. First of all,
system during aging. Yet much uncertainty remains, given the single HBOT protocols vary widely, making it difficult to compare and inte
source of data and current lack of direct clinical evidence. More research grate different results. Moreover, updates on published clinical protocols
is needed to further confirm the significance of mild hyperbaric oxygen are warranted so as to accommodate the general aging populations
for the musculoskeletal system in different animal models of aging, and rather than currently approved indications. Therefore, a generally
ultimately, in the elderly. applicable HBOT protocol needs to be defined in the subsequent step.
In addition to disuse osteoporosis simulated by unloading, a more In recent years, HBOT has been used for various new medical con
common type of osteoporosis in the elderly arises from aging-related ditions with protocols based on lower oxygen pressure (2 ATA or less)
dyshomeostasis of bone metabolism. Interestingly, previous studies on and more daily sessions (40–60 sessions) [194]. One specific emerging
complete spinal transection have demonstrated beneficial effects of protocol, which utilizes repeated intermittent hyperbaric exposures, can
HBOT on bone metabolism, which in turn lead to increased bone lead to a series of changes in the aging populations including tran
hardness and flexibility [187,188]. These results have helped establish scriptome changes [21], telomere elongation [42], cognitive
9
enhancement [140], skin rejuvenation [27], and pulmonary function the work reported in this paper.
parameters improvement [194]. The protocol includes 60 daily HBOT
sessions of 100% oxygen at 2 ATA for 90 min with intermittent air Acknowledgments
breaks. Through a mechanism previously referred to as the
hyperoxic-hypoxic paradox, it induces physiological effects that classi This work is financially supported by grants from the Innovative
cally occur in hypoxia state, excluding an increase in mitochondrial Research Team of High-level Local Universities in Shanghai (SHSMU-
metabolism by activation of SIRT1 [19,85]. These findings will lay a ZDCX20210400) and Shanghai Municipal Key Clinical Specialty
solid foundation for further research. Another protocol, a modified (shslczdzk00901) to QL, and National Natural Science Foundation of
version of HBOT called mild hyperbaric oxygen, provides appropriately China (NSFC) (31871380, 82130045) to YS.
high atmospheric pressure and 35–40% oxygen [197]. Although not
within the usual definition of HBOT, this therapy has been shown to Abbreviations
reverse degenerative changes in skin [154,159], bone [186], muscle
[183,184] and metabolism [169] in experimental animals, primarily by HBOT hyperbaric oxygen therapy
promoting oxidative metabolism [197]. Despite its great potential ATA atmosphere absolute
demonstrated in preclinical studies, there is still a lack of supporting ROS reactive oxygen species
data from clinical trials regarding this modified version of therapy. In SASP senescence-associated secretory phenotype
vestigators need to further determine not only the efficacy and sus HIF-1 hypoxia-inducible factor-1
tainability of existing protocols, but also the dose-response curves RNS reactive nitrogen species
related to oxygen pressure, exposure time, frequency of intervals and VEGF vascular endothelial growth factor
number of sessions in order to optimize treatment conditions. Also, the EPCs endothelial progenitor cells
optimal age range for HBOT to yield significant protective effects against Nrf2 nuclear factor E2-related factor 2
aging needs to be described. SIRT1 sirtuin1
Concerns about the adverse effects of HBOT remain, possibly due to SA-β-gal senescence-associated β-galactosidase
the exposure to a special atmospheric environment. Indeed, HBOT D-gal D-galactose
cannot be considered an entirely benign intervention because of the risk MMPs matrix metalloproteinases
of some mild complications during HBOT, including claustrophobia, SPC stem/progenitor cell
barotrauma and visual effects [3,198]. Fortunately, the vast majority of MSCs mesenchymal stem cells
subjects can recover spontaneously from common complications and CBF cerebral blood flow
serious complications are fairly exceptional, suggesting that the current AD Alzheimer’s disease
procedure is relatively safe [198]. Despite the guaranteed safety, the VD vascular dementia
acceptable rate of side effects may be even lower when targeting healthy UV ultraviolet
aging populations rather than patients with specific pathologies. In DKD diabetic kidney disease
determining an applicable protocol of HBOT for healthy aging, the po ABP arterial blood pressure
tential benefits must be carefully weighed against the corresponding
risks, and the cost if necessary. To put it another way, HBOT may be References
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Redox Biology 53 (2022) 102352

Contents lists available at ScienceDirect

Hyperbaric oxygen therapy for healthy aging: From mechanisms

process as well. Before we discuss the therapeutic mechanisms of HBOT

therapy (HBOT) is a competitive candidate.

neurotherapeutic effects, one of which is enhanced cognitive function. photoaging.

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