**Abstract**

The hippocampus is an integral portion of the limbic system and executes a critical role in spatial and recognition learning, memory encoding, and memory consolidation. Hippocampal aging showed neurobiological alterations, including increased oxidative stress, altered intracellular signaling pathways, synaptic impairment, and organelle deterioration such as mitochondrial dysfunction. These alterations lead to hippocampal cognitive decline during aging. Therefore, the search for new non-invasive therapies focused on preserving or attenuating age-related hippocampal memory impairment could have of great impact on aging, considering the increasing life expectancy in the world. Red light Transcranial LED therapy (RL-TCLT) is a promising but little explored strategy, which involves red light LED irradiation without surgical procedures, safe and at a low cost. Nevertheless, the precise mechanism involved and its real impact on age-related cognitive impairment is unclear, due to differences in protocol, wavelength applied, and time. Therefore, in this chapter, we will discuss the evidence about RL-TCLT and its effects on the hippocampal structure and function, and how this therapy could be used as a promising treatment for memory loss during aging and in age-related diseases such as Alzheimer's Disease (AD). Finally, we will mention our advances in Red 630-light-Transcranial LED therapy on the hippocampus in aging and AD.

**Keywords:** aging, hippocampus, memory, LED therapy, mitochondria

## **1. Introduction**

Aging is a biological process characterized by a general decline in cell function. Life expectancy is increasing and has turned aging into a social problem in the world. The brain is one of the organs that is most affected by age [1, 2], therefore new investigations into safe and non-invasive treatments to reduce age-related brain damage and subsequent cognitive impairment are of critical importance. The aging brain displays synaptic alterations that negatively affect cognitive capacity, especially memory. The hippocampus mediates the formation of new memories and agerelated hippocampal dysfunction compromises learning and memory processes [3].

Interestingly, in hippocampal memory loss, mitochondrial dysfunction plays a central role. Synaptic and mitochondrial dysfunction are early events in aging, mutually influenced, triggering age-associated memory defects [4]. Then, the need arises to find new strategies that can help elderly people to pass a better old age, without forgetting their memories or their history.

A promising but little explored strategy is the application of non-invasive cell stimulation with specific light types. Photobiomodulation is the use of light to stimulate or regenerate organs and tissues. Red-near-infrared (800-1100 nm) and red (600 nm) wavelengths of light-emitting diodes (LED) have been used for a range of therapeutic purposes [5–7]. These wavelengths could penetrate through the skin and have the potential to improve the cellular function of compromised tissue [5, 7]. Red-near-infrared and red LED therapy involves the interaction of photons with molecules in the cells [5, 8, 9]. Specifically, Transcranial LED therapy (TCLT) defines the limited application of LED therapy to the brain. The LED light travels through the layers of the scalp and skull to reach brain cells [10–12]. The brain is commonly irradiated with red (RL) or near-infrared (NIR) light (600- 1100 nm), with a total output power of 1-10,000 mW, a power density that has no thermal effects [9]. Several studies have reported the use of brain irradiation with red or near-infrared (600-1100 nm) LED improving tissue repair, blood flow, cicatrization, and recovery following trauma [12–14]; however, the results are variable due to differences in protocols and wavelengths, LED potential, stimulation time the tissue target, the animal model used, as well as the doses or treatment period [13, 15–17].

Diverse experimental and clinical studies have been performed to test transcranial LED therapy with promising results in brain function [9, 14, 16]. Thus, *in vivo* studies using 660 nm and 810 nm Red-light Transcranial LED therapy (RL-TCLT) in a mice model of aging induced by D-galactose in BALB/c mice improved spatial memory and increased mitochondrial function [18]. In transgenic AD mice, RL-LED treatment of the whole body recovered interstitial fluid flow, reduced Aβ deposition in the brain, and alleviate cognitive deficits [19]. Furthermore, studies in patients victims of severe traumatic brain injury (TBI) showed positive effects after RL-TCLT, enhancing their quality of life, by improving their memory, and decreasing affections such as pain, depression, nervousness, and insomnia (**Figure 1**) [12, 20, 21].

Also, complementary *in vitro* studies with 600–850 nm LED irradiation showed light absorption by the cytochrome c oxidase (COX) enzyme, the complex IV of the oxidative phosphorylation (OXPHOS) system located in the electron transport chain (ETC) from the mitochondria [5], leading to the upregulation of the mitochondrial respiratory capacity and increased ATP production [4, 22]. *In vitro* assays also propose that mitochondrial COX act as a photoreceptor that mediates the beneficial effects of photobiomodulation [23]. Nevertheless, until is unclear how COX mediates the beneficial effect regulating energy production, and for this reason, most of the reports concluded that the mechanism underlying the neuroprotective actions of RL-TCLT is not completely understood. More studies are required to determine the biological events that lead to neuroprotection or neuronal repair.

In this chapter, we will summarize the evidence about the studies using Red Light Transcranial LED therapy (RL-TCLT), mainly focused on their positive effect in the brain, and particularly in the hippocampal structure and function. In addition, we will discuss the possible mechanisms involved in the beneficial effects of RL-TCLT, putting particular emphasis on the mitochondria. Finally, we will briefly comment on our main finding using RL-TCLT, as a potential antiaging therapy.

*Transcranial Red LED Therapy: A Promising Non-Invasive Treatment to Prevent Age-Related… DOI: http://dx.doi.org/10.5772/intechopen.100620*

### **Figure 1.**

*Beneficial effects of red and near-infrared light on the brain. Diverse reports have shown that irradiation of the brain with red and near-infrared light improves different conditions, including cerebral aging and age-related memory loss, stroke, depression, neurodegeneration in several neurodegenerative diseases, pain and trauma, tissue repair and cicatrization, and atrophy among others.*
