
|
Mechanism |
Primary Target |
Molecular/Cellular Effect |
Biological
Outcome |
Relevance in Aging Tissues |
References |
|
Photon
absorption |
C y t o c h r o m e coxidase (CCO) |
Activation of electron transport chain |
Initiation of PBM response |
Reduced
efficiency in aged mitochondria → requires optimized dosing |
8,10 |
|
ATP production ↑ |
Mitochondria |
Increased oxidative phosphorylation |
Enhanced cellular energy metabolism |
Restores impaired bioenergetics in aged
cells |
11,12 |
|
ROS
modulation |
Mitochondria / cytoplasm |
Transient increase in
signaling ROS |
Activation of redox- sensitive pathways |
Helps rebalance oxidative stress in aging |
13 |
|
Gene activation |
NF-κB, AP-1 |
Upregulation of transcription and
protein synthesis |
Cell survival and proliferation |
Supports regeneration in aged tissues |
14 |
|
Anti- inflammatory response |
Cytokines (TNF-α, IL-1β, IL-10) |
↓ Pro-inflammatory,
↑ anti- in- flammatory mediators |
Reduced inflammation |
Counteracts “inflammaging” |
12 |
|
Angiogenesis |
VEGF, endothelial cells |
Increased vascular signaling |
New blood
vessel formation |
Improves oxygenation in aged tissues |
15,16 |
|
Collagen synthesis |
Fibroblasts |
Increased extracellular matrix
production |
Tissue remodeling and repair |
Enhances skin and wound
healing in elderly |
17 |
2.4. Biphasic dose response
One of the main features of PBM therapy is the presence of the
biphasic dose-response relation, which is well described by the Arndt-Schulz law. According to the law, small doses
of light activate biological processes, while large
doses may suppress the physiological functions of cells. Thus, the nonlinear
dependency reflects the presence of a special window of therapeutic
action when phototherapy shows
its positive effect.
At lower energies, no effects may be observed
since there is no adequate response from the biological system, while at high energies, cell activation
is suppressed.
Biphasic behavior is especially important
in elderly patients whose metabolism and optical
properties differ significantly from those in young organisms. Thus, strict
regulation of all parameters of irradiation (wavelengths, irradiance, fluence
and time of irradiation) is critical for success in PBM therapy18.
3. Mechanisms of Photo biomodulation in Aging
The mode of action for Photo biomodulation therapy relies on several
mechanisms, which include photochemical reactions, biochemical reactions and
cellular actions. In the context of aging tissue, PBM acts through the
restoration of bioenergetics in cells, regulation of redox signaling, modulation of the immune
response and stimulation of regeneration in tissues. (Table 2) provides an overview of some of the physiological
pathways involved in the action mechanism of photo biomodulation therapy, while
Figure 2 describes how the optical energy distribution affects aging tissues.
3.1. Mitochondrial activation and restoration of cellular bioenergetics
A major pathway in PBM is the uptake of photons at wavelengths
between 600 nm and 1,100 nm into mitochondria by photo acceptors, specifically cytochrome c oxidase. This facilitates enhanced
electron transport and increases mitochondrial membrane potential19.
As aging occurs, mitochondrial metabolism decreases, reducing energy levels and repair rates for tissues.
PBM acts on the mitochondria to help regenerate
cell division and migration as well as metabolic reactions. Also, PBM can
result in the separation of NO from cytochrome c oxidase, thus facilitating
oxidative phosphorylation and oxygen metabolism20.
3.2. Modulation of reactive oxygen species and redox signaling
ROS have a dual impact on biological organisms, as they can act as
destructive substances as well as messengers. PBM induces a controlled increase
in ROS levels that will activate redox-responsive signaling pathways and
transcription factors, including NF-κB and AP-1. Oxidative stress is often high
in older organisms; however, their protective antioxidants may be weakened. PBM works by balancing ROS levels and improving
cell adaptation as well as antioxidant activity in general. It is essential to
maintain control over ROS because this process helps regulate gene expression
and other functions21,22.
3.3. Anti-inflammatory and immunomodulatory effects
One of the features of aging is the chronic low-grade state of inflammation in the body, called
“inflammaging.” PBM downregulates the production of pro-inflammatory molecules,
such
as, TNF-α, IL-1β and cyclooxygenase-2, while upregulating
anti-inflammatory cytokines such as, IL-10.
Moreover, PBM regulates the activity of immune cells, mainly
affecting the process of macrophage polarization and inducing the conversion of
macrophages from M1 phenotypes to M2 phenotypes. This leads to the resolution of inflammation
and remodeling of tissues, which
is extremely important
in cases when the body is aged23,24.
3.4. Stimulation of proliferation, angiogenesis and Tissue regeneration
PBM improves the function of important cell types responsible for tissue repair, such
as fibroblasts, keratinocytes, endothelial cells and stem or progenitor cells. This results in enhanced cell
proliferation, migration and production of extracellular matrix, which in turn
increases tissue regeneration
capacity25,26. Additionally, PBM
induces angiogenesis by increasing the expression of growth factors
like VEGF and TGF-β. Such
actions increase blood flow, oxygen supply and
nutrition delivery, which can be hampered in aging tissues. All of these biological
mechanisms contributing to tissue regeneration are outlined in (Table 2).
Table 2: Mechanistic pathways of photobiomodulation (PBM) and their biological relevance
in aging tissues.
|
Mechanism |
Primary Target |
Key Biological Effects |
Relevance in Aging Tissues |
References |
|
M i t o c h o n d r i a l activation |
Cytochrome c oxidase (CCO) |
Enhanced
electron transport, ↑ ATP production, improved mitochondrial membrane potential |
Restores impaired cellular bioenergetics and
metabolic activity in aged cells |
27 |
|
Nitric oxide photodissociation |
CCO–NO complex |
Release of inhibitory NO, improved oxygen utilization and respiration |
Enhances mitochondrial efficiency under
hypoxic or aged
conditions |
28 |
|
ROS modulation |
Redox-sensitive
signaling pathways |
Transient ROS increase → activation of NF-κB, AP-1,
antioxidant response |
Rebalances
oxidative stress and restores
redox homeostasis |
20,29,30 |
|
Anti-inflammatory regulation |
Cytokines (TNF-α, IL-1β, IL-10) |
↓ Pro-inflammatory mediators, ↑ anti- inflammatory
cytokines |
Reduces chronic inflammation (inflammaging) |
31 |
|
M a c r o p h a g e polarization |
Immune cells
(M1 → M2) |
Shift toward
reparative phenotype, enhanced tissue remodeling |
Promotes resolution of inflammation and healing in elderly tissues |
32 |
|
Cellular proliferation |
Fibroblasts, keratinocytes |
↑ Cell
proliferation, migration, collagen synthesis |
Accelerates delayed wound healing
in aging |
33-35 |
|
Angiogenesis |
VEGF, TGF-β
pathways |
↑ Neovascularization, improved blood supply |
Enhances oxygen
and nutrient delivery to aged tissues |
36-38 |
|
Stem cell
activation |
Mesenchymal stem cells (MSCs) |
↑ Differentiation and regenerative capacity |
Compensates for age-related decline in stem cell
function |
7,39,40 |
|
Optical–tissue interaction |
Tissue chromophores (melanin, Hb,
water) |
Light absorption, scattering, depth- dependent fluence
distribution |
Alters effective dose delivery in aged
tissues |
41-43 |
|
Biphasic dose response |
Cellular metabolic response |
Stimulation at optimal dose, inhibition at excessive dose |
Requires precise
dosimetry in geriatric applications |
18,44-46 |
3.5. Optical and biophysical considerations in aging tissue
Moreover, besides biological factors, the success of PBM therapy is
significantly dependent on the physics of light transport through tissue. With
age, the physical parameters of tissue change due to alterations in collagen structure, hydration, vascularity and chromophore concentration. This
impacts the optical properties of tissues by affecting absorption, scattering
and anisotropy.
(Figure 2(A)) clearly indicates that the intensity of light diminishes from
maximum values at the surface to lower levels at increasing depths. Moreover,
in (Figure 2(B)), it can be observed that fluence is exponentially related
to depth according to the effective attenuation
coefficient (μeff). Consequently, optical changes with age impact the depth of light
penetration into tissue47-49.
Figure 2: Penetration and fluence
distribution of light
used for photobiomodulation therapy in aging tissues.
Fluence distribution map obtained by Monte Carlo simulation demonstrating light intensity
distribution in a multilayer tissue model, where the absorption is maximal at
the surface layer while the light intensity decreases with depth.
Fluence profile as a function of depth depicting the exponential
decrease in light intensity due to the effective attenuation coefficient (μeff).
3.6. Biphasic dose-response relationship
PBM exhibits a biphasic dose-response relationship response
where small doses cause increased cell activity while large doses can cause
inhibition, with the optimum dose giving the maximum effect. The biphasic
effect of PBM is especially important during use on aged individuals who have
lower metabolic abilities, hence
altering their sensitivity to light. Thus, proper optimization of optical
parameters is necessary for an efficient and
optimized application during treatment of older individuals. Understanding the
physiology of aging and using this information along with optical theory helps
determine the correct treatment procedure50-53.
Despite considerable research into the physiological pathways
involved in photobiomodulation, notable variations can be seen among various
experimental setups. While a large number of researchers have observed improved
mitochondrial function and ATP generation due to exposure to PBM, others have
reported limited or no significant effects based on the wavelength, light intensity and biological conditions of cells54,55.
In addition to the above, the involvement of cytochrome c oxidase as the main photo acceptor
is also disputed, with certain
researchers proposing that it could
involve other molecules such as the water bound to the mitochondria or other
chromophores. The differences suggest that PBM physiology varies among
different tissues and ages.
Hence, there is a need for an extended mechanism that will factor in
the aforementioned differences in order to achieve accurate predictions of PBM
results in aging tissues.
4. Optical Interaction with Aging Tissue
The therapeutic effectiveness of PBM is regulated by both cellular
responses as well as light propagation inside biological tissues. Optical
changes related to aging can have a significant impact on the way in which
light propagates inside biological tissues,
thus impacting the amount of light that can be effectively
delivered, as seen in Figure 2 below. Parameters of light propagation are
highlighted in (Table 3).
4.1. Age-related changes in tissue optical properties
Tissue composition is significantly altered with the process of
aging. These changes in tissue composition directly impact the optical
characteristics. The changes
include decreased water content, changes in the structure of collagen and changes in the concentration of chromophores such as melanin and hemoglobin.
All these changes impact the basic optical parameters such as the absorption coefficient (μₐ), scattering coefficient (μ↑) and the anisotropy factor (g)56.
Changes in the structure of collagen with the process
of aging include increased
collagen cross-linking and disorganization. These changes impact the scattering
characteristics. Similarly, changes in tissue pigmentation and vascularization impact
the absorption characteristics57,58. The changes
in tissue composition with the process of aging
increase the optical heterogeneity of the tissue, which impacts the propagation
of photons.
4.2. Light attenuation and fluence distribution
The propagation of light in biological tissues is affected by
absorption and scattering phenomena. Consequently, there is exponential
attenuation as light travels deeper into tissues. This can be characterized as follows:
?(?) = ? ?−????? … . (?)
Where I (z) represent light intensity at a depth z, I0 represents incident light intensity and μeff represents effective attenuation coefficient. The effective attenuation coefficient can be characterized as follows:
? = √?? (? + ? ′) … . (?)
Where μs′ = μs (1-g) is the reduced scattering coefficient.
As seen from Figure 2(B), fluence falls off sharply with depth, suggesting that a substantial fraction of optical energy is lost to absorption and scattering in the outer layers of tissue. In aged tissues, the enhanced scattering effect causes even greater attenuation of the beam.
4.2. Monte carlo modeling of photon transport
accurate description of the phenomenon. Therefore, the Monte Carlo (MC) simulation has been recognized as the gold standard in the simulation of photon transport59,60.
This approach considers the simulation of the path of single photons as they experience multiple scattering and absorption. The spatial distribution of the MC simulation is presented in Figure 2(A), where the distribution of the photon fluence decreases from the surface with depth. Moreover, the MC simulation offers the possibility of simulating the realistic multi-layer model of the tissue involved. This makes the MC simulation highly appropriate for the simulation of the aging tissues involved.
4.3. Implications for PBM dosimetry in aging
The optical properties of aging tissues have significant implications for PBM dosimetry. As illustrated in Figure 2(A-B), the energy deposition becomes superficial, while the fluence at the deeper layer is greatly reduced. Hence, it is crucial for PBM protocols in geriatric medicine to consider these changes in optical properties by appropriately modifying the parameters used in PBM, including the wavelengths, power density and exposure time52,61. The optical parameters relevant for light propagation and their implications in aging tissues are listed in (Table 3).
4.4. Optimization strategies
Optimization methods for dealing with the problem of light attenuation in aging tissues include:
• Utilization of long wavelength light (800-980 nm) for increased penetration
• Modification of surface fluence to account for attenuation loss at increasing depths
• Utilization of Monte Carlo based simulation models for treatment planning
•Tailored PBM therapy according to tissue or patient specificity
All of these optimization techniques lead to greater light control and PBM efficacy.
Table 3: Optical parameters and their impact on photo biomodulation in aging tissues.
|
Parameter |
Description |
Effect in Aging Tissues |
Impact on PBM |
References |
|
(µa) (absorption coefficient) |
Light absorption by chromophores (melanin, hemoglobin, water) |
Altered chromophore distribution
with age |
Modifies energy deposition profile |
43,62,63 |
|
(µs) (scattering coefficient) |
Photon scattering within tissue microstructure |
Increased due
to collagen cross-
linking and structural changes |
Reduces penetration depth |
62,64,65 |
|
(g) (anisotropy factor) |
Directionality of scattering |
Slight variation with tissue aging |
Influences photon propagation direction |
62,66,67 |
|
(µeff) (effective attenuation coefficient) |
Combined absorption and scattering effects |
Increased in aging tissues |
Accelerates light attenuation |
67,68 |
|
(Φ)
Fluence |
Optical energy
per unit area within tissue |
Reduced at deeper layers |
Limits therapeutic effectiveness in deeper tissues |
68,69 |

Figure 3: Photobiomodulation (PBM) applications in geriatrics
medicine. Scheme illustrating the connections between the biological
processes initiated via PBM and its therapeutic effects.
Light activation of mitochondrial chromophores increases the
production of ATP and ROS signaling, which results in regulation of
inflammatory responses, neovascularization and tissue regeneration.
5.1. Chronic wounds and ulcers
Chronic wounds like diabetic foot ulcers and pressure ulcers are common among geriatric patients
because of poor vascularization,
chronic inflammation and inability for regeneration. PBM promotes wound healing
through cellular proliferation, inflammation reduction and angiogenesis by
elevating levels of VEGF [70–72].
PBM has also been shown to improve wound healing by
increasing the expression of vascular endothelial growth factor (VEGF), thus
improving wound microcirculation. PBM has also been shown to improve wound
healing by improving the inflammatory response, thus improving the transition
from the inflammatory phase to the proliferative phase of wound healing73.
5.2. Musculoskeletal disorders
Musculoskeletal disorders, including osteoarthritis and joint pain, are significant sources
of disability in the elderly.
PBM has therapeutic effects
in treating musculoskeletal disorders by its anti-inflammatory and analgesic properties, which are achieved by its antioxidant properties in
reducing oxidative stress and inflammatory mediators23,74.
PBM also has effects in improving microcirculation and tissue oxygenation, as well as its effects in improving chondrocyte
function and maintenance of the cartilaginous matrix. This makes PBM an effective adjunctive therapy
in the management of geriatric musculoskeletal disorders21,75.
5.3. Neurodegenerative disorders
Neurodegenerative diseases such as Alzheimer’s
and Parkinson’s disease
have a significant association
with mitochondrial dysfunction, oxidative stress and neurodegeneration. PBM
therapy, especially transcranial PBM therapy, has shown promise as a
neuroprotective therapy for neurodegenerative diseases76.
PBM therapy increases
mitochondrial activity in neurons,
increases blood flow to the brain and decreases neuroinflammation. These mechanisms have shown promise in improving cognitive functions
and neurological outcomes. However, more clinical studies are necessary to
prove the long-term effects and
treatment protocols for PBM therapy for neurodegenerative diseases.
5.4. Skin aging and dermatological applications
Skin aging is characterized by reduced collagen synthesis, decreased
elasticity and degradation of skin structures. PBM has been used for
therapeutic purposes in dermatology for rejuvenation and repair of tissues.
The therapeutic effects
are mediated by enhanced
fibroblast proliferation and collagen synthesis due to increased mitochondrial activity and growth factor secretion.
PBM therapy increases microcirculation and reduces oxidative stress for
improved skin texture, elasticity and dermal structures. Clinical
studies have shown
significant improvement in reducing wrinkles and improving skin quality
after PBM therapy.
5.5. Integration of clinical evidence
Even though photo biomodulation proves to be widely applicable as a
therapy tool in many clinical conditions, inconsistency in therapy
parameters such as wavelength,
fluence, irradiance and exposure
time is an issue. The lack of uniformity
in dosimetric parameters makes comparing different clinical trials rather
challenging.
As can be seen from (Figure
3), the effectiveness of the therapy is directly
related to certain
biological mechanisms associated with activation, regulation of mitochondrial activity and changes
in redox balance
and inflammation. ( Table 4) summarizes the main
applications of PBM in geriatric medicine, the mechanisms that work behind each
application and therapeutic effects observed.
Table 4: Clinical applications of photo biomodulation in geriatric patients.
|
Application |
Mechanism of Action |
Key Biological Targets |
Clinical Outcomes |
References |
|
Chronic wounds
and ulcers |
↑ ATP production, ↑ VEGF, ↓ inflammation |
Fibroblasts, endothelial cells, cytokines |
Accelerated wound healing, enhanced angiogenesis,
improved tissue remodeling |
74,77 |
|
Musculoskeletal disorders |
↓ oxidative stress, ↓ inflammatory mediators, ↑
microcirculation |
Chondrocytes, synovial cells |
Pain reduction, improved joint mobility, enhanced functional recovery |
78 |
|
Neurodegenerative disorders |
↑ mitochondrial function, ↑
cerebral blood flow, ↓
neuroinflammation |
Neurons, microglia |
Improved cognitive performance, neuroprotection,
enhanced neuronal survival |
79 |
|
Skin aging and dermatology |
↑ fibroblast proliferation, ↑ collagen synthesis, ↑ growth factor signaling |
Dermal fibroblasts, extracellular matrix |
Improved skin elasticity, wrinkle
reduction, dermal regeneration |
80 |
Although PBM has shown positive results in clinical settings, its
effectiveness varies among different studies. Factors such as wavelength,
fluence, irradiance and exposure time are different across studies, making it
hard to compare the results. Some
studies show that similar parameters used in PBM therapy may produce varied
results, proving that there is no clear
guideline in the use of PBM
therapy.
Furthermore, clinical studies may be flawed due to factors such as a
small number of participants, inadequate control groups and insufficient follow-ups, leading to unreliable results. The heterogeneous characteristics of the population also make it difficult to interpret the results.
Therefore, the current studies should be improved by conducting
extensive clinical studies and developing a uniform dosimetric guideline for
PBM therapy.
6. Dosimetry and Therapeutic Parameters
Photo biomodulation (PBM) therapy is greatly influenced by dosimetry
accuracy. Parameters such as the wavelength, irradiance, fluence, duration of exposure and frequency should be precisely manipulated in order to attain favorable physiological effects. This becomes
especially significant in aged tissue owing
to the presence of changes in optical properties and metabolism that affect both the
penetration and biological activity of light.
One unique characteristic of photo biomodulation therapy is its dose-dependency, which can be
observed through the nonlinear interaction of light energy on biological processes. The dose-response relationship is depicted in (Figure 4), whereas
the dosimetric parameters involved
in photo biomodulation therapy and their importance in medical practice are detailed
in (Table 5).
6.1. Wavelengths
The wavelength chosen determines how deep the light can penetrate
into the tissue as well as the extent of the absorbance by the chromophores. Red light (630 - 660 nm) and near infrared (800 - 980 nm) are normally used
in PBM treatments43. Red
wavelengths of light have high absorbance and therefore are used for
dermatology purposes and wound treatment; on the other hand, near infrared
light has deeper
penetration and hence is best used to treat internal
tissues such as muscles and joints.
6.2. Power density (Irradiance)
Irradiance, which is measured in mW/cm², describes how quickly
energy can be administered to the tissue. This factor becomes important because very low irradiance would
not have any effect on the cells, while high irradiance
can cause inhibition.
The importance of the irradiance level should be taken into account
together with the duration of exposure, because it will define the amount of energy. In that regard,
it becomes important to optimize the irradiance level
in order to remain within the therapeutic range.
Figure 4: Biphasic nature of the dose response and depth- dependent fluence attenuation for photo biomodulation.
A biphasic nature of the dose-response relationship with demonstration of the
Arndt-Schulz law and optimal therapeutic window.
Depth-dependent fluence attenuation with exponential decrease of
intensity as a result of light absorption and scattering.
6.3. Fluence (Energy density)
Fluence or the amount of energy per unit area (J/cm²) is another very important factor in PBM therapy and is calculated as follows:
??????? = ????? ??????? × ????
????… . (?)
Typical values for fluence are in the 1-10 J/cm² range for
superficial treatments and in the 50–100 J/cm² range for deep tissues.
Nevertheless, due to the absorption and scattering process, surface fluence
does not indicate energy delivery into deeper tissue levels.
|
Parameter |
Definition |
Typical Range |
Clinical Relevance |
References |
|
Wavelength (nm) |
Light spectral range used for PBM |
630–660 (superficial), 800–980 (deep) |
Determines penetration depth and chromophore absorption |
81 |
|
Power density
(mW/cm²) |
Power delivered per unit area |
5–500
mW/cm² |
Controls rate of energy
delivery and cellular
stimulation |
44 |
|
Fluence (J/cm²) |
Energy delivered per unit area |
1–10 (superficial),
10–100 (deep) |
Determines therapeutic dose
and effectiveness |
82 |
|
Exposure time (s–min) |
Duration of irradiation |
Seconds to minutes |
Influences total delivered energy |
33 |
|
Treatment frequency |
Number of
sessions |
2–5
sessions/week |
Determines cumulative therapeutic response |
83 |