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 functions^21,22.  

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 aged^23,24.  

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 capacity^25,26. 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. 

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 tissue^47-49.


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 procedure^50-53.

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 cells^54,55.

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 characteristics^57,58. 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 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 transport^59,60.

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 time^52,61. 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

5. Clinical Applications of Photobiomodulation in Geriatrics  
Photobiomodulation (PBM) has become a highly prospective non-invasive method of treating various aging- related pathologies. Due to its capacity to affect mitochondrial functioning, oxidative stress and inflammation, photobiomodulation becomes an effective way to influence the most important pathological mechanisms of tissue dysfunction related to aging. The connection between biological effects caused by photo biomodulation and clinical results can be seen in (Figure 3); whereas clinical uses of PBM are described in (Table 4).

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.