Aging of lymphoid organs: Can photobiomodulation reverse age-associated thymic involution via stimulation of extrapineal melatonin synthesis and bone marrow stem cells?

Abstract

Thymic atrophy and the subsequent reduction in T-cell production are the most noticeable age-related changes affecting lymphoid organs in the immune system. In fact, thymic involution has been described as "programmed aging." New therapeutic approaches, such as photobiomodulation (PBM), may reduce or reverse these changes. PBM (also known as low-level laser therapy) involves the delivery of non-thermal levels of red or near-infrared light that are absorbed by mitochondrial chromophores, in order to prevent tissue death and stimulate healing and regeneration. PBM may reverse or prevent thymic involution due to its ability to induce extrapineal melatonin biosynthesis via cyclic adenosine monophosphate (AMP) or NF-kB activation, or alternatively by stimulating bone marrow stem cells that can regenerate the thymus. This perspective puts forward a hypothesis that PBM can alter thymic involution, improve immune functioning in aged people and even extend lifespan.

Keywords: age-related thymic involution; bone marrow stem cells; extrapineal melatonin biosynthesis; low-level laser therapy; photobiomodulation; signaling pathways; thymus regeneration.

Figure 1

Structure of the thymus

Figure 2. Age-related thymic involution

The perivascular space (PVS) increases dramatically as sex steroid production increases with age, and T-cell production falls with age. ETP = early T cell progenitor cells; TN = CD3, CD4, CD8 triple negative T cells; DP = CD4+, CD8+ double positive T cells; SP = CD4+ or CD8+ single positive T cells.

Figure 3. Mechanism of PBM stimulation of extrapineal melatonin biosynthesis

ATP produced after PBM causes more cAMP leading to activation of protein kinase a and stabiization of AANAT. The burst of ROS from the mitochondria can activate protein kinase d which phosphorylates IkB and leads to proteasomal degradation. The released NF-kB travels to the nucleus where it activates gene transcription of AANAT. The increased enzyme activity of AANAT leads to biosynthesis of more melatonin from tryptophan that can rejuvenate the thymus.

Figure 4. Mechanism of PBM stimulation of bone marrow stem cells for thymus regeneration

PBM using different wavelengths of light is absorbed by chromophores within the cell, activates secondary messengers (ATP, ROS and Ca²⁺⁾ that go on to activate signaling pathways in bone marrow stem cells. This causes the cells to leave their hypoxic niche and proliferate. When exposed to cues from the aging thymus, these progenitor cells can replenish the T-cell production.