What Is Inflammaging? The Role of NAD+ in Chronic Inflammation and Aging

Key Takeaways

• Inflammation is essential for survival, but when it becomes chronic and low-grade, it can drive tissue damage, aging, and disease.
• Inflammaging describes this age-related, background inflammation, and it is now viewed as a central biological link between aging and conditions like heart disease, type 2 diabetes, neurodegeneration, and obesity.
• NAD+ is not only crucial for cellular energy; it also helps keep inflammatory pathways in check, and its age-related decline both contributes to and results from chronic inflammation.
• Early studies suggest that boosting NAD+ with precursors like nicotinamide riboside (NR) can lower inflammatory markers in the blood and dampen overactive immune responses in different groups of people.
• These findings are promising, but we still do not know exactly how much they matter for long-term health in otherwise healthy adults, so more research is needed before drawing firm conclusions.

Inflammation is one of the body’s most important defense systems—but it comes with a catch. The same mechanisms designed to protect the body from injury and infection can, over time, contribute to its gradual decline. This is the paradox at the heart of inflammation: it’s the immune system’s most powerful frontline defense, essential for eliminating threats and initiating repair—without it, even minor injuries like paper cuts could become life-threatening. But over time, this tightly regulated process can become dysregulated, shifting from a protective mechanism to a source of persistent damage.

This shift is at the core of “inflammaging,” a state of chronic, low-grade inflammation that develops with age, reflecting the body’s ability to find the inflammatory “off switch.”¹ This silent, sustained inflammatory response lingers, leading to tissue damage and dysfunction. Importantly, inflammation is not the enemy. Although inflammaging is a common underlying factor in many age-related conditions,² including cardiovascular disease, type 2 diabetes, and neurodegenerative disorders, the challenge is not inflammation itself, but rather how well it is regulated. 

Researchers are increasingly interested in what controls that balance, and one molecule has come into focus: nicotinamide adenine dinucleotide (NAD+).³ Known for its role in cellular energy production, NAD+ also helps to regulate inflammatory pathways.³ As NAD+ levels decline with age, this regulatory capacity may weaken. Emerging research suggests that restoring NAD+ levels—through precursors such as nicotinamide riboside (NR)—may help reduce markers of inflammation.⁴ In this article, we explore how inflammation changes with age, the role of NAD+ in regulating this process, and the clinical evidence behind its potential impact on inflammatory markers.

What Is Inflammation? How Your Immune System Protects and Destroys

Inflammation is the body’s built-in response to stress, injury, or infection—a tightly coordinated process carried out by the immune system to protect and repair. When this process is activated, it produces the classic signs of inflammation: redness, heat, swelling, pain, and sometimes a temporary loss of function. These symptoms are visible signs of a complex cascade of events happening beneath the surface, involving immune cells, chemical messengers, and changes in blood flow. 

At its core, inflammation is not a single event, but a dynamic process. How that process is initiated, regulated, and resolved ultimately determines whether it supports healing or contributes to harm. 

Acute vs. Chronic Inflammation: Why One Heals You and One Ages You

Not all types of inflammation are the same—and the difference between acute and chronic inflammation is what drives whether it helps or harms. Acute inflammation is the short-term, protective response that most people are familiar with, such as when a cut becomes red and swollen or a sprained ankle expands to twice its size. In these cases, the immune system rapidly sends signals and resources to the affected area to contain damage, eliminate potential pathogens, and begin the repair process. Once the threat is neutralized and healing begins, the acute inflammatory response subsides, typically within a few days. 

Conversely, chronic inflammation is prolonged, low-grade, and often not visible.⁵ It can persist long after a threat subsides—or even come about with seemingly no trigger at all. In some cases, the immune system becomes hypersensitive, overactive, or misdirected, as in allergies or autoimmune diseases⁶—both of which can drive inflammation for months or years. A growing body of research suggests that chronic inflammation is also shaped by lifestyle choices and environmental factors,⁷ including diet, physical activity, sleep, stress, and toxin exposure.⁸ This form of inflammation is particularly insidious, as it may not produce any obvious symptoms, yet can contribute significantly to tissue damage, aging, and disease over time.

What Is Inflammaging? The Hidden Link Between Chronic Inflammation and Aging

Inflammaging is a term coined by immunologist Claudio Franceschi in 2000 to describe this chronic, low-grade inflammation that is not triggered by a specific pathogen or injury, but instead appears to be a feature of the aging process itself.⁹ Over time, a range of biological changes promote a more pro-inflammatory state, including the accumulation of cellular damage, oxidative stress, mitochondrial dysfunction, and senescent cells that secrete inflammatory signals.¹⁰

One key player in this process is the NLRP3 inflammasome, a multi-protein complex within immune cells that detects cellular stress and damage.¹¹ Although it’s essential for defense, NLRP3 activity appears to increase with age, amplifying inflammatory signaling even in the absence of an infection or trigger. This creates a self-reinforcing cycle, where chronic inflammation accelerates cellular aging, which in turn generates more signals that further promote inflammation. Over time, this feedback loop can contribute to a wide range of age-related conditions¹¹—but because inflammation is so tightly intertwined with such diseases, it’s challenging to determine whether it’s a root cause, a consequence, or both. 

Clinically, inflammaging has emerged as one of the most important links between aging and chronic disease, as it’s now considered a central biological mechanism underlying conditions ranging from heart disease and type 2 diabetes to neurodegenerative disorders and obesity.⁵ Therefore, it’s also a key target in efforts to promote healthier aging and longevity. Increasingly, researchers are exploring the molecular systems that regulate this process, including pathways influenced by NAD+, as potential levers to help restore balance.

The Connection Between NAD+ and Inflammation

NAD+ is a critical coenzyme found in every cell, best known for its role in cellular energy metabolism.¹² Beyond this, emerging research is positioning NAD+ as a central regulator of the inflammatory process.¹³ Notably, NAD+ levels decline with age and consistent exposure to metabolic stressors such as poor diet, excessive alcohol intake, and sun exposure. This decline is hypothesized to be both a contributor to and a consequence of inflammaging, making the relationship between NAD+ and inflammation fundamentally bidirectional. Research has shown that chronic inflammation itself has been linked to reduced NAD+ levels—and this connection may be driven in part by how NAD+ is used in the body.¹⁴

NAD+ serves as a co-substrate for three key enzyme families that are activated during inflammatory and metabolic stress: CD38 glycohydrolases, poly(ADP-ribose) polymerases (PARPs), and sirtuins. Among these, CD38 is considered a primary driver of inflammation-induced NAD+ depletion.¹⁵ Its expression increases with both age and sustained inflammation, meaning that the more inflamed the cellular environment, the more rapidly NAD+ is consumed. At the same time, age-related genomic instability activates PARPs, which further drain NAD+ stores while competing directly with sirtuins for the same diminishing pool.¹⁶

As NAD+ levels drop, sirtuin activity becomes impaired.¹⁷ This is particularly significant because sirtuins play a key role in regulating inflammation and maintaining cellular homeostasis. The result is a reinforcing cycle, where chronic inflammation accelerates NAD+ depletion, while low NAD+ levels reduce the cell’s ability to control inflammation. This bidirectional relationship has made NAD+ restoration an increasingly compelling target for breaking the cycle of inflammaging. 

Does Increasing NAD+ Reduce Inflammation? Here’s What the Clinical Research Shows

Given the close relationship between NAD+ decline and chronic inflammation, researchers have increasingly explored whether restoring NAD+ levels can help interrupt this cycle. Several NAD+ precursors have been studied for their effects on inflammation, but the findings have not been consistent across compounds. For example, clinical studies of niacin have reported reductions in some inflammatory markers, including C-reactive protein (CRP) and TNF-α, although these effects are thought to occur largely through activation of the GPR109A receptor rather than through increases in NAD+ itself.¹⁸ In contrast, two studies of nicotinamide (NAM) found no significant effect on CRP levels.¹⁸ Evidence for nicotinamide mononucleotide (NMN) is also limited. One study reported reduced inflammatory signaling following exercise, but the authors noted that this may not necessarily be beneficial, as exercise-induced inflammation is thought to play a role in promoting exercise-induced adaptations.¹⁹

Among NAD+ precursors, nicotinamide riboside (NR) has been the most extensively studied in the context of inflammation. One of the earliest indications of its anti-inflammatory potential came from experiments in human-derived cells, which showed that increasing NAD+ levels could decrease inflammatory signaling.²⁰ Since then, a growing body of clinical research has examined NR supplementation across a range of diverse populations, including healthy older adults,⁴ as well as individuals with cardiovascular disease,²¹ obesity,²² autoimmune disorders such as lupus²³ and psoriasis,²⁴ and neurodegenerative conditions, including Parkinson’s disease.²⁵

Although study designs, participant characteristics, and outcome measures have varied considerably, a broadly consistent pattern has emerged: NR supplementation is frequently associated with reductions in key markers of inflammation. These markers include signaling molecules such as inflammatory cytokines—proteins like IL-6, TNF-alpha, and IL-1β that act as messengers to promote inflammation,²⁶ as well as pathways like the previously mentioned NLRP3 inflammasome. In some cases, NR supplementation has also been associated with reduced reactivity of immune cells, meaning the cells are less likely to overrespond to inflammatory triggers.²³ Summaries of the individual studies are provided in the table below. 

Taken together, these findings suggest that increasing NAD+ may help turn down the overall intensity of inflammatory signaling at multiple levels. Nevertheless, it’s important to interpret these results with appropriate caution. While reductions in inflammatory markers have been observed fairly consistently, it’s not yet clear what these changes mean for long-term health consequences, especially in otherwise healthy individuals. More research is still needed to determine whether these shifts translate into meaningful long-term health benefits. 

Table 1. Summary of peer-reviewed, published NR studies demonstrating an anti-inflammatory effect in humans.