Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks

Aging is closely linked to chronic inflammation, immune system changes, and disruptions in circadian rhythms, all of which contribute to age-related diseases. In the study Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks, Hardeland et al. explore how melatonin, a hormone primarily known for regulating sleep, also plays a crucial role in modulating inflammation. The study highlights melatonin’s ability to act as both a pro- and anti-inflammatory agent depending on cellular and disease contexts, with many of its effects mediated by SIRT1, a key protein in aging and immune regulation. By analyzing various research findings, the authors discuss how melatonin influences immune responses, circadian rhythms, and microRNAs, providing insights into its potential therapeutic applications and risks in aging-related conditions.

As we age, our bodies undergo many changes, including a decline in melatonin production. Melatonin is a hormone best known for regulating sleep, but it also plays an important role in our immune system and inflammatory responses. According to the study, “Aging and various age-related diseases are associated with reductions in melatonin secretion, proinflammatory changes in the immune system, a deteriorating circadian system, and reductions in sirtuin-1 (SIRT1) activity.”

Inflammation is a natural response that helps our body fight infections and heal injuries. However, chronic inflammation, also known as inflammaging, is a key factor in many age-related diseases, including Alzheimer’s, diabetes, and cardiovascular conditions. Melatonin is unique because it can act as both a pro-inflammatory and anti-inflammatory agent, depending on the situation. This means it has the potential to help or harm the body, depending on the disease and the conditions in which it is used.

Scientists have also found that SIRT1, a protein linked to longevity, works closely with melatonin to control inflammation. The study suggests that many of melatonin’s effects “are abolished by inhibiting SIRT1, indicating mediation by SIRT1.” This connection may explain why melatonin plays a role in aging and immune function.

This scientific review brings together past research on how melatonin interacts with inflammation, aging, and immune function. The author examines multiple studies conducted in cell cultures, animal models, and human subjects to analyze melatonin’s role in the immune system. The paper focuses on:

• How melatonin regulates both pro- and anti-inflammatory pathways
• The connection between melatonin and SIRT1, a key aging-related protein
• The impact of melatonin on circadian rhythms and immune function
• How melatonin influences microRNAs (miRNAs), small molecules that regulate gene activity

By reviewing these different areas, the study provides a comprehensive understanding of how melatonin may affect inflammation and aging.

One of the most interesting findings is that melatonin does not always behave the same way —it can either increase or decrease inflammation, depending on the situation. In some cases, melatonin stimulates the release of inflammatory cytokines such as IL-1β, IL-6, and TNF-α, particularly in immune cells like macrophages and T-helper cells. This pro-inflammatory effect has been observed in conditions like rheumatoid arthritis, where melatonin appears to worsen symptoms.

On the other hand, melatonin can also suppress inflammation by blocking key inflammatory pathways, including NLRP3 inflammasome activation, nitric oxide release, and NF-κB signaling. The study highlights that melatonin’s effects are context-dependent, meaning its role changes based on the body’s state and the specific disease.

SIRT1 is an essential protein that helps regulate aging, inflammation, and metabolism. The study found that melatonin activates SIRT1, which in turn suppresses inflammation. According to the study, “A perhaps crucial action may be the promotion of macrophage or microglia polarization in favor of the anti-inflammatory phenotype M2.” SIRT1 helps turn off harmful inflammatory signals and supports antioxidant defense mechanisms, which protect cells from damage.

Studies show that many of melatonin’s anti-inflammatory benefits disappear when SIRT1 is blocked, confirming that SIRT1 is a key player in this process. Interestingly, in cancer cells, melatonin has the opposite effect—it actually reduces SIRT1 activity, which may help stop tumor growth. This means that melatonin’s impact on SIRT1 is not one-size-fits-all, and its effects vary depending on the cell type and disease.

Macrophages are immune cells that can be classified into two types. M1 macrophages fight infections but can also contribute to excessive inflammation, while M2 macrophages are responsible for tissue repair and reducing inflammation.

The study found that melatonin encourages macrophages to shift from M1 to M2, helping to lower chronic inflammation. This effect is particularly important in aging, where excessive inflammation contributes to tissue damage and age-related diseases.

Melatonin is closely linked to our circadian rhythms, the natural 24-hour cycle that regulates sleep and other biological functions. Disruptions in circadian rhythms—such as poor sleep—can increase inflammation and accelerate aging. As melatonin levels naturally decline with age, circadian rhythms become weaker, leading to increased inflammation.

The study highlights that melatonin and SIRT1 work together to maintain healthy circadian rhythms, which helps control inflammation. Some age-related diseases, including Alzheimer’s, are linked to disrupted sleep and circadian rhythm disturbances, suggesting that melatonin supplementation might help prevent these conditions.

MicroRNAs (miRNAs) are small molecules that help regulate gene expression. The study found that melatonin influences several miRNAs that control inflammation, with some increasing inflammation and others reducing it. Melatonin’s ability to regulate miRNAs may explain its dual effects on inflammation. This discovery suggests that future therapies could target specific miRNAs to control melatonin’s effects more precisely.

Melatonin’s ability to both increase and decrease inflammation makes it a powerful but unpredictable tool for treating diseases.

• Potential Benefits: Melatonin may help with Alzheimer’s, metabolic syndrome, and heart disease by reducing chronic inflammation.
• Possible Risks: Melatonin could make symptoms worse in autoimmune diseases like rheumatoid arthritis and multiple sclerosis by stimulating immune responses.
• Metabolic Diseases: There is still debate about whether melatonin is helpful or harmful for type 2 diabetes in humans, as its effects seem to vary between species.

Overall, melatonin has enormous therapeutic potential, but more research is needed to determine when it should and should not be used.

This study provides valuable insights into how melatonin interacts with aging, inflammation, and immune regulation. It highlights that melatonin is not just a sleep hormone—it plays a critical role in controlling inflammation, supporting circadian rhythms, and regulating immune function. However, melatonin’s effects are complex and highly context-dependent. While it has anti-inflammatory benefits in some conditions, it can also worsen inflammation in others, such as autoimmune diseases.

Future research should focus on identifying when melatonin is beneficial versus harmful, understanding its interactions with SIRT1 and miRNAs, and exploring how circadian rhythms influence inflammation and aging. For now, melatonin remains a promising but complex tool for managing aging and inflammation. Understanding its dual nature will be key to developing safe and effective treatments in the future.