Introduction
During the aging process, humans become more susceptible to metabolic diseases such as type 2 diabetes, sarcopenia, neurodegenerative diseases, and cardiovascular diseases. Mitochondrial dysfunction is currently recognized as one of the major mechanisms contributing to the development of age-related diseases. Age-associated impairment of mitochondrial function contributes to reduced ATP production, increased oxidative stress, and disturbances in cellular homeostasis [2, 3].
These alterations are accompanied by elevated levels of intramyocellular lipids (IMCL), increased production of inflammatory mediators such as TLR2, TNF-α, and IL-1β, and chronic low-grade inflammation, all of which may promote insulin resistance and metabolic dysfunction [4, 5].
PBM, also known as low-level laser (or light) therapy (LLLT), is a non-invasive application of red to infrared light on body tissues. It utilizes non-ionizing and low-power light sources (laser or LED), and narrow-spectrum (usually 600–1000 nm) light [6]. The pioneering work of Endre Mester demonstrated the biological effects of low-level laser irradiation, stimulating further research into PBM applications [7].
Since then, PBM has been investigated in numerous experimental and clinical studies and has shown potential to reduce oxidative stress, modulate inflammation, and improve mitochondrial metabolism [8]. Many of the reported therapeutic effects of PBM have been linked to its capacity to modulate mitochondrial activity, thereby influencing ATP synthesis, oxidative stress responses, and cellular metabolism [9, 10]. As a result, PBM has gained increasing attention as a promising therapeutic strategy for age-related disorders and has found applications in contemporary medical practice [11].
Although the role of mitochondrial dysfunction in aging is well established, there is still a lack of research linking core mitochondrial processes and newly discovered non-canonical pathways, such as TRPV1-mediated calcium signaling, to their function in age-related diseases and multi-organ pathologies. This review aims to address this knowledge gap by providing an updated, integrated perspective on the therapeutic potential of PBM in age-related disorders.
Cellular and Mitochondrial Mechanisms of PBM
Photobiomodulation refers to the modulation of cellular function at a biological level induced by red and near-infrared (NIR) light. At the cellular level, PBM is strongly associated with a mitochondrial response, although, as recent research shows, effects are not limited exclusively to mitochondria [12, 13]. Even though the exact process is still unclear and under research, it has been shown that mitochondrial stimulation using red and near-infrared (NIR) light causes increased adenosine triphosphate (ATP) production, reduction of oxidative stress, as well as cell signalling and growth factor synthesis [14].
PBM may also cause a controlled and transient increase in reactive oxygen species (ROS). ROS may act as signaling mediators, which, at high concentrations and with long-term exposure, may cause cellular damage; at low, controlled concentrations and short exposure, they are beneficial. Preclinical evidence suggests that during this stimulated ROS increase, activation of the transcription factor nuclear factor kappa B (NF-kB) occurs, which may function as a redox-sensor and be beneficial in the maintenance of homeostasis [15].
Nevertheless, the biological role of NF-kB is context-dependent, as excessive or chronic activation may also contribute to inflammation [15]. The acquired knowledge regarding photobiomodulation has led to its application in the treatment of numerous diseases, such as diabetes, neurodegenerative disorders, and pain management [10].
Aging is a progressive process associated with the dysfunction of many organelles and the disruption of cellular homeostasis. One of the key factors influencing the aging process is mitochondrial dysfunction. Mitochondria play a central role in ATP production through oxidative phosphorylation, which is required for cellular metabolic processes [2].
Mitochondrial dysfunction plays an important role in aging because it leads to impaired ATP synthesis, as well as disruptions in redox balance and calcium homeostasis. As cells age, the process of mitophagy becomes impaired, which leads to the accumulation of defective mitochondria. Damaged mitochondria may contribute to reduced ATP production, disturbances in the regulation of apoptosis, increased ROS production, and defective calcium signaling.
Increased mitochondrial calcium uptake and excessive oxidative stress may disrupt mitochondrial membrane potential and increase mitochondrial membrane permeability, which may lead to the apoptotic cascade. Excessive ROS may damage mitochondrial proteins, lipids, and DNA, further aggravating mitochondrial dysfunction and promoting the activation of apoptotic pathways. Reduced ATP production is particularly relevant in organs with high energy demand, such as the brain, liver, skeletal muscle, and cardiovascular system.
In these tissues, reduced ATP production and impaired OXPHOS may contribute to age-related metabolic diseases. It has been observed that reduced ATP production and changes in mitochondrial oxidative phosphorylation (OXPHOS) significantly affect the development of insulin resistance, MASLD, and type 2 diabetes (T2D) in older patients [2, 3].
Taking into account the importance of mitochondrial function in cellular processes, preservation of mitochondrial homeostasis is crucial for longevity and for preserving health during the aging process [2].
Growing evidence suggests that the main element of mitochondria involved in the mechanism of photobiomodulation is cytochrome c oxidase (CCO)—a terminal enzyme of the mitochondrial electron transport chain [10]. Studies indicate that wavelengths in the range of 600–810 nm are absorbed by the enzyme cytochrome c oxidase [16]. Cytochrome c oxidase is unit IV of the mitochondrial electron transport chain.
Its function is to transfer one electron from each of four cytochrome c molecules to a single oxygen molecule. As a result of this reaction, two molecules of water are formed. This process also leads to the generation of a proton gradient, because four protons required for this process are translocated across the mitochondrial membrane.
This electrochemical gradient enables the production of chemical energy in the form of adenosine triphosphate (ATP) by the ATP synthase enzyme, which is necessary to meet the energy demands of key cellular processes [17]. Although CCO is considered one of the main mitochondrial photoacceptors involved in PBM, recent evidence suggests that the positive effects of PBM may also involve additional signaling pathways.
The mechanism of PBM in mitochondria is based mainly, though not exclusively, on its interaction with CCO. Due to photobiomodulation, there is an increase in mitochondrial ATP production, which provides the necessary energy for cellular regenerative processes and triggers signaling pathways, including processes associated with cyclic GMP (cGMP). These processes are linked to nitric oxide, the production of which also increases thanks to PBM.
Secondary to the increased production of cGMP, vasodilation occurs, thereby enhancing tissue perfusion and the regenerative potential of cells [18].
In recent years, studies on PBM have shown that it is suitable for the therapy and treatment of deeper tissues. PBM has demonstrated positive effects in reducing oxidative stress, improving mitochondrial function, enhancing ATP production, and modulating inflammatory responses. All of these factors may contribute to tissue regeneration.
It has also been observed that PBM plays a role in enhancing blood flow and reducing inflammation. PBM induces a controlled release of ROS, which act as second messengers for multiple signaling pathways responsible for cellular repair and regeneration. ROS can also activate transcription factors such as NF-kB and hypoxia-inducible factors (HIFs), which play important roles in regulating inflammation, angiogenesis, and cellular proliferation [18].
Beyond the classic cytochrome c oxidase and AMPK-dependent pathway, emerging evidence highlights that photobiomodulation may regulate cellular metabolism through parallel ion channel-mediated mechanisms. For instance, Tong et al. (2025) demonstrated that PBM can increase intracellular Ca2⁺ influx via activation of the transient receptor potential vanilloid 1 (TRPV1) channel.
Elevated intracellular Ca2⁺ subsequently leads to a controlled increase in reactive oxygen species (ROS), which modulates mitochondrial activity and promotes cell proliferation in a dose-dependent way. Significantly, pharmacological inhibition of TRPV1 prevents these PBM-induced alterations in Ca2⁺ signaling, ROS production, and mitochondrial function. These data indicate that TRPV1-Ca2⁺-ROS signaling complements traditional mitochondrial pathways, providing a clearer insight into how PBM regulates cellular bioactivity [13].
Optimization of Photobiomodulation Parameters and Biphasic Dose Response
In PBM therapy, appropriate consideration of treatment parameters such as power density, wavelength, exposure time, and session frequency is essential. These dimensions must be adjusted according to the cell type and its mitochondrial content, as different cells exhibit various responses.
Most commonly used wavelengths in PBM are within the spectrum of red and near-infrared light, which is approximately 600–700 nm for red light and 770–1200 nm for near-infrared, as presented in Fig. 1.Fig. 1Red and near-infrared light therapy range created in BioRender.
Hryniewicz, W. (2026) https://BioRender.com/9858n3u
The most commonly used devices for photobiomodulation are lasers and LED lamps [10]. The penetration of light through tissue is defined by both absorption and scattering by the structures and molecules in the tissue. A key concept in PBM is the biphasic dose response, often described with reference to the Arndt-Schulz principle.
As stated by this model, the biological response to PBM is not linear. An optimal range of treatment parameters may stimulate mitochondrial activity, cellular signaling, and tissue repair, whereas suboptimal parameters fail to induce a measurable biological effect. Excessive exposure does not provide a better response: it reduces the beneficial effect or even inhibits cellular function.
This mechanism may be explained by the fact that PBM affects many interconnected intracellular processes. It is believed that this biphasic effect may be explained by an excessive, overexposure-dependent increase in ROS generation, excessive NO production, activation of some cytotoxic pathways, and excessive activation of NF-kB. Within the proper therapeutic window, PBM may increase ATP production, reduce oxidative stress, enhance cell signalling and growth factor synthesis, stimulate mitochondrial electron transport, and improve mitochondrial membrane potential, whereas too low exposure may be insufficient to activate these pathways [19].
Moreover, PBM results depend not only on wavelength, but also on treatment frequency, fluence (energy density expressed in J/cm2), which is determined by irradiance (expressed in mW/cm2) and exposure time. Tissue characteristics determine target values of these parameters20,21. Studies have shown that cells with high mitochondrial density, including macrophages, neurons, and muscle cells, respond optimally to wavelengths in the range of 660–808 nm, with the exposure time typically lasting from several seconds to a few minutes, suggesting the high sensitivity of these cells to PBM, contributing to its therapeutic effects.
In contrast, cells such as fibroblasts, osteoblasts, or keratinocytes require PBM with a broader range of wavelengths, extending from approximately 420 to 980 nm. The exposure frequency should also be individualized and must be aligned to the patient’s clinical condition, as there is currently no consensus on standardized repetition protocols [22]. Patients with age-related cognitive impairment could benefit from photobiomodulation within the 650 to 1064 nm range.
Furthermore, the use of a single, specific wavelength may lack sufficient efficacy in treating cognitive decline associated with neurodegenerative diseases [23].
It is crucial to avoid excessively high doses or power densities, as it may result in a biphasic effect, inhibiting the therapeutic effect. Safety studies have shown differences in the range of therapeutic applications of light-emitting diode–red light (LED-RL), which may depend on skin pigmentation and other tissue characteristics. For example, one study reported that in LED-RL exposure, individuals with skin of color tolerated doses of up to 320 J/cm2, while non-Hispanic Caucasian individuals tolerated doses of up to 480 J/cm2 [24].
However, these values should not be generalized as universal PBM doses, because effective and safe parameters depend on the treated tissue and exposure protocol.
Photobiomodulation in Type 2 Diabetes: Evidence from Human Glucose Studies and Mitochondrial Mechanisms
Red light therapy has been investigated in relation to type 2 diabetes treatment due to its capacity to modulate systemic blood glucose levels. In a major study conducted by Jeffery et al., thirty healthy participants underwent an oral glucose tolerance test (OGTT) with a 75 g glucose load. Forty-five minutes prior to glucose administration, half of the participants were treated with 670 nm photobiomodulation at an intensity of 40 mW/cm2 during a 15-min session, applied over the upper back (800 cm2).
The remaining half served as a sham-control group, undergoing the same procedure but with an inactive light source. Capillary blood glucose level and end-tidal CO2 (EtCO2) were measured every 15 min over a 2-h period. Notably, participants exposed to active PBM exhibited an overall reduction in blood glucose level of 7.3% compared to the sham group.
This metabolic response is likely driven by PBM-induced activation of cytochrome c oxidase—the resulting primary mitochondrial alterations may optimize systemic insulin homeostasis and sensitivity to this hormone20. Although the measurement of CO2 expiration showed no significant differences between the research groups, EtCO2 markedly increased when comparing the 670 nm PBM intervention with the participants’ control visit [25].
However, recent meta-analyses on this topic found inconclusive results regarding metabolic and inflammatory outcomes; nonetheless, PBM has demonstrated strong therapeutic efficacy in the management of painful diabetic peripheral neuropathy [26].
PBM therapy also may exert beneficial metabolic effects by modulating mitochondrial processes within adipose tissue. These findings are particularly relevant to type 2 diabetes mellitus, as free fatty acids released during the lipolysis process can impair insulin signaling in key metabolic organs, including the liver, skeletal muscle, and pancreatic β-cells. Age-related mitochondrial dysfunction may aggravate this process, leading to chronic insulin resistance and metabolic disorders.
In preclinical models, PBM (635 nm, 8 J/cm2) significantly decreases the release of free fatty acids from adipose tissue. Simultaneously, there is an elevation of mitochondrial reactive oxygen species (ROS), which inhibits the phosphatase PTEN and activates the kinase AKT. Enhanced AKT activity causes inhibition of FoxO1, resulting in decreased expression of crucial lipolytic enzymes and reduced triglyceride hydrolysis, lowering plasma levels of FFA and TG.
These mechanisms may have important implications for age-related metabolic disorders, including type 2 diabetes mellitus. Although the available evidence suggests that PBM may modulate mitochondrial bioenergetics and intracellular signaling pathways, these findings are primarily derived from in vitro and animal studies and require further well-designed clinical trials to confirm their translational relevance in humans [27].
Neuroprotective Effects of Photobiomodulation in Neurodegenerative Disorders
In recent years, a growing amount of preclinical research has highlighted the importance of mitochondrial function in relation to improving therapeutic outcomes in neurodegenerative diseases. Conditions such as Alzheimer’s and Parkinson’s diseases are the most prevalent of them and are characterized by progressive neuronal loss, leading to significant cognitive and motor impairments. These impairments are strictly associated with irreversible progressive neuropathologies, which makes the treatment options very limited and focuses on slowing disease progression rather than achieving recovery.
Besides that, currently used pharmacological treatments provoke various side effects, which significantly aggravate patients’ quality of life. These limitations were the primary motivation for researchers to develop new therapeutic approaches.
With regard to Alzheimer’s disease, clinical evidence based on studies in human patients remains limited. Most of the available data comes from in vitro experiments or animal models. Nevertheless, these studies have provided valuable insights into the potential mechanism by which PBM may improve Alzheimer’s treatment, including reduced β-amyloid accumulation, decreased tau protein hyperphosphorylation, decline of neuroinflammation and neuronal apoptosis, and improvements in cognitive function.
In terms of cognitive outcomes, PBM has been shown to enhance memory and learning in animal models, as demonstrated by behavioral assessments such as the Morris water maze test [28]. Nevertheless, one study on the efficacy and safety of transcranial PBM for mild cognitive impairment due to Alzheimer’s disease showed a statistically significant improvement in K-MoCA scores after 13 weeks of therapy [29].
In contrast, a greater body of evidence is available for Parkinson’s disease, with a growing number of both in vitro and in vivo studies [30]. These studies consistently indicate that red light therapy should be associated with improved mitochondrial function in dopaminergic neurons and improved motor function. Furthermore, PBM has demonstrated neuroprotective effects, including preservation of dopaminergic neurons in the substantia nigra pars compacta (SNc) [28].
In a randomized clinical study conducted by Santos et al., patients with idiopathic Parkinson’s disease at Hoehn and Yahr stages 1–2 received transcranial PBM using a 670 nm LED applied over the temporal area twice a week over nine weeks. Compared with the placebo group, participants who underwent PBM treatment demonstrated a significant improvement in gait performance, as assessed by the fast 10-m walk test. In subsequent studies conducted by Liebert et al., the efficacy of transcranial, abdominal, and nasal PBM was evaluated.
These studies reported significant improvements in cognitive functions, fine motor skills, balance, and gait. Outcomes were assessed using standardized tests: Montreal Cognitive Assessment (MoCA) and Timed Up and Go (TUG). In a subsequent study, PBM was administered solely to the abdominal region.
Nevertheless, the therapeutic outcomes remained similar to the previous study. These findings suggest that irradiation of the cranium may not be a necessary condition for successful therapy. More recent clinical research, carried out by Bicknell et al., pointed out the PBM influence on intestinal microbiome, precisely improvements in the Firmicutes-Bacteroidetes ratio, increased abundance of anti-inflammatory short-chain fatty acid-producing bacteria, and a decrease of potentially pro-inflammatory taxa.
This study establishes an association between photobiomodulation and the gut-microbiome-brain axis in Parkinson’s disease and suggests a potential systemic, disease-modifying effect of PBM [30]. However, small cohort sizes, heterogeneous irradiation parameters, and a lack of long-term follow-up data currently limit the broad clinical translation of these neuroprotective outcomes.
Photobiomodulation Therapy in Metabolic-Associated Steatotic Liver Disease (MASLD)
MASLD, previously referred to as non-alcoholic fatty liver disease (NAFLD), is closely associated with insulin resistance, obesity, and age-related mitochondrial dysfunction. Biological aging is known to reduce cellular ATP production and increase oxidative stress, leading to lipid metabolism disorders that promote the development of hepatic steatosis. Since the pathogenesis of MASLD is strongly linked to the dysfunction of mitochondria, therapies that modulate their function represent a promising strategy, particularly for the elderly.
In this context, photobiomodulation is a particularly valuable non-invasive approach to improve metabolic processes. In mouse models, PBM (635 nm, 8 J/cm2) effectively reduces hepatic lipid accumulation, improves insulin sensitivity, and reduces weight gain. These effects are mediated by the activation of AMP-activated protein kinase (AMPK) through Ca2⁺/calmodulin-dependent kinase kinase β (CaMKKβ), causing suppression of the nuclear translocation of SREBP1 and inhibition of aberrant hepatic lipogenesis [31].
Furthermore, researchers have uncovered an additional mechanism by which PBM may exert its beneficial effects in MASLD, focusing on the interaction between mitochondria and the endoplasmic reticulum (ER). In MASLD, the integrity of mitochondria-associated membranes (MAMs) is disrupted, which contributes to ER stress, mitochondrial dysfunction, and hepatocyte lipotoxicity. MAMs are specialized structures responsible for maintaining connections between mitochondria and the ER.
Notably, PBM restores MAMs integrity, consequently enhancing ER-mitochondria contact and improving mitochondrial homeostasis. Moreover, PBM increases the expression of mitofusin 2 (Mfn2), while simultaneously reducing the levels of PERK and CHOP, leading to attenuation of ER-stress-mediated hepatocyte damage [32].
Consistent with preclinical findings, a recent randomized clinical trial provides evidence supporting the potential therapeutic effects of photobiomodulation as an adjunct therapy in MASLD. Obese older adults (65–75 years old) with MASLD were treated with low-level laser therapy (660 nm) in combination with a Mediterranean diet. Compared with the control group receiving the Mediterranean diet alone, patients undergoing PBM demonstrated significantly greater improvements in liver enzyme levels, lipid profile, body mass index, and waist circumference [33].
Photobiomodulation in Skeletal Muscle Regeneration
PBM is also being investigated as a non-invasive method to stimulate skeletal muscle regeneration. While skeletal muscle injuries affect individuals throughout life, age-related sarcopenia, volumetric muscle loss (VML), and progressive mitochondrial decay represent critical challenges in the elderly population [18, 34]. The Global Burden of Disease study from 2021 indicated that 1.686 billion musculoskeletal disorders (MSDs) were registered in that year [35].
Age-related loss of muscle strength—sarcopenia affects up to 50 million people worldwide. Muscle injuries require long-term treatment and expensive rehabilitation, often limiting work capacity for years. With age, the regenerative capacity declines progressively.
Mitochondrial dysfunction is considered one of the key mechanisms contributing to age-related sarcopenia [18]. Efficient muscle regeneration is therefore crucial to enhance quality of life, reduce medical costs, and improve clinical outcomes.
Skeletal muscle regeneration is particularly dependent on the proper functioning of satellite cells (muscle stem cells), whereas the remodeling of muscle cells by these cells is governed by the microenvironment and their metabolic health. The metabolic health of these cells is contingent on the functional capacity of their mitochondria. In addition to ATP production, mitochondria regulate redox signaling, calcium homeostasis, and cellular differentiation pathways.
All of these processes are involved in muscle regeneration—a highly energy-demanding process that becomes progressively impaired with age due to mitochondrial dysfunction. It should be noted that the role of mitochondria in muscle regeneration is not dependent solely on ATP—mitochondria can also provide important regulatory signals to muscle stem cells during muscle regeneration34. Preclinical studies suggest that PBM may stimulate satellite cell activation, proliferation, and myogenic differentiation, thereby supporting the formation of new muscle fibers during regeneration [18, 36].
Furthermore, PBM induces a transient increase of ROS that acts as a signal to recruit myogenic precursor cells, crucial for skeletal muscle repair. PBM also induces the release of growth factors, such as VEGF and basic fibroblast growth factor (bFGF). These growth factors contribute to neovascularization and sustain the proliferation of myoblasts.
Enhanced angiogenesis improves oxygen and nutrient delivery to regenerating tissues and may facilitate more effective muscle repair. Although current evidence is promising, most studies have been performed in animal models or experimental systems, and further clinical studies are needed to establish optimal PBM protocols for skeletal muscle regeneration in older individuals. These mechanisms may be particularly relevant in aging, where impaired mitochondrial function, chronic low-grade inflammation, and reduced regenerative capacity contribute to delayed muscle repair [18, 34].
Photobiomodulation in Cardiovascular Aging
The use of PBM is being explored as a potential treatment for cardiovascular aging. The importance of research in this field remains crucial, as cardiovascular diseases represent the leading cause of death globally, with over 19 million deaths per year [37]. These illnesses often involve chronic inflammation and oxidative stress, which are the targets of PBM [38].
There is extensive research on PBM in animal models. A longitudinal study in mice found the therapy to be beneficial for left ventricular wall thickness, left atrial dimension, aortic diameter, thoracic aorta, distensibility, and pulse wave velocity [39]. It is also reported that the treatment can increase the left ventricular ejection fraction and reduce the aortic wall stiffness in mice [40].
In hypertensive patients, PBM has the potential to be an adjunct therapy. It can increase nitric oxide levels in blood vessels, promoting vasodilatation. A meta-analysis of clinical and pre-clinical studies suggests that this may help to lower systolic and diastolic blood pressure, mean arterial pressure, and heart rate; however, the certainty of the evidence is low due to a high risk of bias [41].
PBM can be of use in acute conditions, such as myocardial infarction. It can help regenerate cells and contribute to forming new blood vessels by increasing the expression of vascular endothelial growth factor [42]. Moreover, the treatment leads to an increase in circulating transforming growth factor beta (TGF‐β1) and reduction in cardiac enzyme markers troponin and creatine phosphokinase.
There have also been some clinical studies conducted on this topic. They found improvements in creatine kinase levels, lactate dehydrogenase levels, white blood cell count, neutrophils and lymphocytes following five days of light transthoracic light application, which may improve clinical outcomes [43]. Translating these promising outcomes into routine clinical use remains a challenge, constrained by non-standardized irradiation protocols, small sample sizes, and a lack of long-term follow-up data.
Photobiomodulation in Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is the leading cause of vision loss [44], and its global prevalence is expected to increase to an estimated 288 million by 204,045. There are two types of AMD: exudative and non-exudative, with the latter accounting for the majority of cases. The accessibility of therapies such as complement inhibitors remains a major challenge in treating the disease [44].
PBM could aid in the management of the non-exudative type by restoring mitochondrial function, upregulating cytoprotective factors, and preventing apoptotic cell death in the affected retinal tissue [46]. Reducing oxidative stress and modulating inflammation would also be beneficial [44].
The research has been significantly advanced by a recent landmark trial, LIGHTSITE III. The study spanned over 24 months, during which the participants were treated with multiwavelength (590, 660, and 850 nm) PBM in six series delivered every 4 months. Each series consisted of 9 sessions over 3 to 5 weeks.
In a total of 100 participants, with 148 eyes treated, the analysis after 13 months found a significant difference in the best corrected visual acuity scores between the PBM and sham treatment groups. The therapy was well tolerated with a low rate of adverse events and high subject compliance [47]. The LIGHTSITE IIIB study, which analyzes therapy outcomes after 24 months, is yet to be published.
Despite these encouraging results, long-term follow-up studies in larger, highly heterogeneous patient populations and standardized treatment guidelines are still required.
Photobiomodulation in the Management of Oral Mucositis
PBM is already used in clinical practice for the management of oral mucositis in patients receiving treatment such as chemotherapy, radiotherapy, or hematopoietic stem cell transplantation [48]. Oral mucositis is a common and debilitating complication of cancer therapy that impairs nutrition, speech, and quality of life and may lead to interruptions in anticancer treatment. The Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO) have incorporated photobiomodulation into their clinical practice guidelines for selected groups of oncology patients.
Current recommendations support the use of intraoral PBM for the prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation or patients receiving radiotherapy, with or without chemotherapy, for head and neck cancers [48].
Safety Profile and Adverse Effects of Photobiomodulation
Common Adverse Effects
PBM is generally considered safe and well-tolerated, although adverse events have occasionally been reported. Reported side effects are typically mild and self-limiting, with fatigue and headache being the most frequently described. These adverse effects have primarily been observed in small patient cohorts and were associated with higher doses or prolonged treatment durations [49].
Low-dose transcranial photobiomodulation (t-PBM) using near-infrared light can cause mild side effects, which were described as headaches, insomnia, irritability, and an ashtray-like taste, although none of the participants discontinued treatment [50]. Individuals with skin of color have been observed to be at higher risk of non-transient hyperpigmentation and thermal-induced pain compared to lighter types of skin [51]. Selected side effects have been illustrated in Fig.
2.Fig. 2Side effects of red light therapy created in BioRender. Hryniewicz, W.
(2026) https://BioRender.com/xfy218v
Oncological Safety Considerations
One of the major concerns associated with PBM is its potential effects on malignant cells in cancerous lesions, with particular emphasis on thyroid cells. PBM should be applied with caution in malignant lesions because its effects on tumor biology remain incompletely understood, and the possibility of influencing cellular proliferation and metabolism cannot be completely excluded. Concerns regarding the potential effects of PBM on malignant cells have largely originated from experimental studies.
However, findings from clinical studies have been reassuring [52]. Current clinical data do not provide sufficient evidence to justify avoiding PBM in patients undergoing cancer therapy, cancer survivors, or individuals at increased oncological risk [49].
Despite the theoretical concerns, available clinical evidence has not demonstrated an increased risk of tumor recurrence or disease progression when PBM is applied according to established protocols [52, 53]. However, long-term follow-up studies remain necessary to further evaluate the oncological safety of PBM.
Study Limitations and Future Prospects of Photobiomodulation
Many studies face challenges related to inter-study comparability. A considerable number of these investigations do not include placebo controls and employ similar PBM parameters in both animal and human studies, even though it requires different PBM parameters [16]. While PBM has shown promising results in treating diabetes and its complications, several studies have reported a lack of efficacy, highlighting the need for further standardized research [54].
Another concern is the limited number of studies that observe long-term effects of PBM and its potential toxicity [55]. It is necessary to gain a deeper understanding of this issue.
PBM represents a promising therapeutic option for a variety of pathological conditions. In the future, it might be recommended for obesity, diabetes, burning mouth syndrome, temporomandibular disorders, tendinopathy, knee osteoarthritis, fibromyalgia, myofascial neck pain, diabetic foot ulcers, age-related cardiovascular problems, androgenetic alopecia, age-related cognitive impairment, major depressive disorder (MDD) and generalized anxiety disorder (GAD) [56, 57]. PBM may also be used as an adjunctive approach in multiple disease conditions in combination with conventional immunomodulatory or diabetes treatments.
Moreover, it has presented possible benefits in reducing inflammation, total cholesterol, and insulin resistance, which are common concerns in the elderly population. The development of personalized approaches based on patient characteristics might be one of the features of this therapy in the future—it could enhance PBM’s effectiveness [58].
In addition, animal studies have shown positive effects of PBM on age-associated cardiovascular remodeling and cardiac dysfunction [40]. These findings highlight the need for human clinical trials to validate these effects in a clinical setting.
Conclusions
Photobiomodulation (PBM) represents a promising, non-invasive adjunctive therapy for the management of age-related diseases. By targeting mitochondrial dysfunction through cytochrome c oxidase and parallel ion channel pathways such as TRPV1, PBM effectively restores ATP production, modulates ROS signaling, and reduces systemic inflammation. This review has summarized current evidence on the effects of PBM on mitochondrial function, modulated cellular signaling, and its therapeutic potential in age-related diseases, with a particular focus on metabolic dysfunction (including type 2 diabetes mellitus), as well as neurodegenerative, cardiovascular, hepatic, ocular, and musculoskeletal conditions, in addition to cancer therapy-related oral mucositis.
However, new trials may lead to fully elucidating the underlying mechanisms of action of PBM. In order to confirm or refute the efficacy of these therapies, it is essential to conduct large-scale, high-quality, and long-term trials. Future research should aim to define optimal treatment parameters.
These studies are crucial for providing definitive evidence of efficacy and enabling the development of standardized PBM protocols. These are essential for the widespread clinical adoption of PBM.