Inflammation and aging: what is inflammaging?

If you ask most people what aging looks like, they'll describe the visible signs: wrinkles deepening around the eyes, hair losing its color, muscles becoming harder to build and easier to lose. These external markers are easy to recognize because they're literally skin-deep. But beneath the surface, a far more insidious process unfolds—one that operates silently for decades, reshaping metabolism, immunity, and cellular function in ways that fundamentally determine how we age.

That process is chronic low-grade inflammation. Not the acute inflammation you experience after an injury or infection—the kind that causes redness, swelling, and pain before resolving completely. This is something different: subtle, persistent, systemic inflammation that never quite goes away. It doesn't announce itself with fever or obvious symptoms. Instead, it quietly accumulates year after year, altering how cells communicate, how tissues function, and how organs age.

Scientists have given this phenomenon a name: inflammaging. Coined by Italian researcher Claudio Franceschi and colleagues in the early 2000s, the term captures a crucial insight—that chronic inflammation isn't just a consequence of aging, but may be one of its fundamental drivers. Understanding inflammaging is essential for understanding aging itself, and more importantly, for identifying evidence-based strategies to slow its progression.

What is inflammaging?

Inflammaging refers to a chronic, low-grade inflammatory state that develops progressively during aging, even in the absence of obvious infection, injury, or autoimmune disease. Unlike the inflammation you experience when you cut your finger or catch a cold—which is acute, localized, and resolves when the threat is eliminated—inflammaging is subtle, systemic, and persistent.

It's characterized by several measurable changes in the immune and metabolic systems:

• Elevated circulating pro-inflammatory cytokines: Small signaling proteins that coordinate immune responses remain chronically elevated
• Increased innate immune activation: The body's first-line defense system stays in a heightened state
• Altered immune cell function: Both innate and adaptive immune cells change their behavior and output
• Persistent activation of inflammatory signaling pathways: Molecular switches like NF-κB remain chronically "on"

The key inflammatory biomarkers most commonly associated with inflammaging include:

• Interleukin-6 (IL-6): Perhaps the most studied inflammaging marker, strongly associated with frailty and mortality
• Tumor necrosis factor alpha (TNF-α): A master inflammatory cytokine involved in systemic inflammation
• C-reactive protein (CRP): A downstream marker of inflammation measured routinely in clinical settings
• Interleukin-1β (IL-1β): A potent inflammatory mediator linked to cellular senescence

Epidemiological studies have repeatedly demonstrated that elevated IL-6 and CRP levels predict morbidity and all-cause mortality in older adults, independent of other risk factors. Research published in the Journal of Gerontology by Ferrucci and colleagues, and cardiovascular studies in Circulation by Ridker and others, have established these associations across diverse populations.

This consistency suggests that inflammation is not merely a passive consequence of aging—it appears to be biologically involved in driving age-related decline itself.

Why does inflammation increase with age?

The rise in inflammatory tone during aging is not caused by a single factor. Rather, it results from multiple interconnected processes that accumulate over time, creating a self-reinforcing cycle of cellular stress and immune activation.

1. Accumulation of cellular damage

Over decades, cells throughout the body accumulate various forms of damage that trigger inflammatory responses:

• DNA damage: From oxidative stress, replication errors, and environmental exposures
• Mitochondrial dysfunction: Damaged cellular powerhouses produce less energy and more reactive oxygen species
• Protein misfolding: The quality control systems that maintain protein integrity become less efficient
• Lipid oxidation: Cellular membranes undergo oxidative damage

When cells experience this accumulated damage, they release signaling molecules known as DAMPs (damage-associated molecular patterns). These molecular distress signals activate the innate immune system, triggering inflammatory responses even in the absence of pathogens. It's as if the immune system is constantly responding to an internal "threat" that never fully resolves.

2. Cellular senescence and the SASP

One of the most important contributors to inflammaging is cellular senescence—the state where cells stop dividing but don't die. While senescent cells initially serve a protective function (preventing potentially cancerous cells from proliferating), they accumulate with age and adopt a highly inflammatory secretory profile.

This secretory pattern is called the senescence-associated secretory phenotype (SASP), and it includes a potent cocktail of inflammatory molecules:

• IL-6 and IL-8 (inflammatory cytokines)
• TNF-α (a master inflammatory regulator)
• Matrix metalloproteinases (enzymes that degrade tissue structure)
• Growth factors that can promote tissue dysfunction

These SASP factors don't stay confined to the senescent cells—they diffuse into surrounding tissues, creating a pro-inflammatory microenvironment that can induce senescence in neighboring cells. Research by Judith Campisi and colleagues, extensively reviewed in the Annual Review of Physiology, has established cellular senescence and the SASP as central drivers of age-related tissue dysfunction.

3. Immune system remodeling

Aging fundamentally alters both arms of the immune system in ways that shift the balance toward inflammation:

• Adaptive immunity declines: T-cell diversity decreases, B-cell function deteriorates, and vaccine responses weaken
• Innate immunity becomes hyperactive: Macrophages, neutrophils, and other innate immune cells become more easily activated and slower to resolve
• Phenotypic skewing: Immune cells shift toward pro-inflammatory subtypes

This paradoxical combination—weakened adaptive responses but heightened innate activation—is sometimes described as "immunosenescence" occurring alongside inflammaging. The immune system becomes less effective at fighting new threats while simultaneously maintaining chronic inflammatory signaling.

Cytokines: the signaling molecules driving inflammaging

Cytokines are small proteins that serve as the communication network of the immune system, coordinating responses to infection, injury, and cellular stress. In young, healthy organisms, cytokine signaling is tightly regulated—it ramps up when needed, then resolves when the threat is eliminated.

In aging, however, this elegant regulatory system becomes dysregulated. Chronic activation of transcription factors like NF-κB—often called the "master switch" of inflammation—leads to sustained cytokine production even in the absence of acute threats.

IL-6, in particular, has emerged as a critical inflammaging biomarker with wide-ranging biological effects. Elevated IL-6 is strongly associated with:

• Cardiovascular disease risk: Including atherosclerosis, heart failure, and vascular dysfunction
• Frailty: The clinical syndrome of weakness, slowness, and vulnerability to stressors
• Muscle decline: Both sarcopenia (muscle loss) and reduced muscle quality
• Cognitive impairment: Including increased risk of dementia and accelerated cognitive decline

Longitudinal cohort studies, including the InCHIANTI study in Italy and the Health ABC study in the United States, have demonstrated that elevated IL-6 predicts functional decline and mortality independent of other established risk factors like diabetes, hypertension, or smoking.

This epidemiological consistency across diverse populations reinforces a crucial point: inflammatory signaling is not just correlated with poor aging outcomes—it appears to be biologically meaningful in driving those outcomes.

CD38: the critical link between inflammation and NAD+ depletion

One of the most important molecular discoveries in inflammaging research has been the identification of CD38 as a bridge between inflammatory signaling and metabolic aging. This connection fundamentally changed how scientists think about the relationship between inflammation and cellular energy metabolism.

CD38 is an enzyme expressed on the surface of immune cells and other cell types throughout the body. While it has multiple functions, one of its most significant roles is as a major NAD+-consuming enzyme—it literally breaks down NAD+ at an accelerating rate.

Groundbreaking research published in Cell Metabolism in 2016 by Camacho-Pereira and colleagues demonstrated several critical findings:

• CD38 expression increases with age across multiple tissues in both mice and humans
• Inflammatory signals directly upregulate CD38—the more inflammation, the more CD38 activity
• Increased CD38 activity leads to progressive NAD+ depletion in tissues throughout the body
• Genetic or pharmacological suppression of CD38 in mouse models preserved NAD+ levels and improved metabolic function

This finding is scientifically profound because it creates a direct molecular pathway connecting inflammation to cellular energy metabolism:

Inflammation → CD38 activation → NAD+ depletion → Mitochondrial dysfunction

It's a vicious cycle: inflammation drives CD38 expression, CD38 degrades NAD+, NAD+ depletion impairs cellular function and stress responses, and impaired cellular function generates more inflammation.

NAD+ depletion as a consequence of inflammaging

NAD+ is not just another cellular metabolite—it's a central regulator of metabolism, stress responses, and longevity pathways. It's required for fundamental processes in every cell:

• Mitochondrial oxidative phosphorylation: The primary pathway for cellular ATP production
• Sirtuin activation: These NAD+-dependent enzymes regulate metabolism, inflammation, and stress resistance
• DNA repair via PARPs: Enzymes that fix DNA breaks consume NAD+ as fuel
• Cellular stress responses: NAD+ availability determines cellular resilience to various stressors

As inflammaging progresses, NAD+ depletion occurs through multiple mechanisms:

• CD38-mediated degradation: The inflammatory upregulation of CD38 directly breaks down NAD+
• PARP activation: DNA damage (which increases with inflammation) activates PARPs, which consume massive amounts of NAD+ for repair
• Increased metabolic demand: Inflammatory stress increases cellular energy requirements

The consequences of this NAD+ depletion create yet another self-reinforcing cycle:

• Impaired mitochondrial efficiency leads to more oxidative stress
• Reduced sirtuin signaling weakens anti-inflammatory pathways
• Altered metabolic flexibility impairs stress responses
• Decreased DNA repair capacity allows more damage to accumulate

Studies published in Cell by Gomes and colleagues (2013) and in Nature Communications have demonstrated that restoring NAD+ levels in aged animal models improves mitochondrial markers, reduces inflammatory signaling, and extends healthspan.

This research establishes that inflammaging is not only about immune dysregulation—it fundamentally alters cellular energy metabolism in ways that accelerate aging across multiple organ systems.

The metabolic consequences of inflammaging

Chronic inflammation doesn't stay confined to the immune system. Its effects cascade throughout physiology, intersecting with multiple hallmarks of aging and contributing to age-related disease.

Insulin resistance and metabolic dysfunction

Pro-inflammatory cytokines, particularly TNF-α and IL-6, directly interfere with insulin signaling pathways. Research by Gökhan Hotamisligil published in Nature established the mechanistic link between inflammation and insulin resistance decades ago, but it remains one of the most important connections in metabolic aging.

This inflammation-insulin resistance connection helps explain why inflammaging is strongly associated with metabolic syndrome, type 2 diabetes, and cardiovascular disease—all conditions that dramatically accelerate biological aging.

Vascular aging and cardiovascular risk

Inflammation impairs endothelial function—the health of the inner lining of blood vessels. Specifically, inflammatory cytokines reduce nitric oxide production, which is essential for vascular elasticity and blood flow regulation.

The result is progressive vascular stiffness, reduced arterial compliance, increased blood pressure, and accelerated atherosclerosis. These changes don't just affect cardiovascular risk—they impact every organ system that depends on adequate blood flow, including the brain.

Muscle decline and sarcopenia

Inflammatory cytokines promote muscle protein breakdown (catabolism) while simultaneously impairing muscle protein synthesis. This double hit contributes significantly to sarcopenia—the age-related loss of muscle mass and strength that predicts frailty, falls, loss of independence, and mortality.

Elevated IL-6 and TNF-α are consistently associated with lower muscle mass and strength in older adults, suggesting that inflammaging is a driver of functional decline, not just a bystander.

Neuroinflammation and cognitive decline

While the brain was once thought to be "immune privileged," we now know that systemic inflammation influences brain function through multiple pathways. Low-grade peripheral inflammation activates microglia (the brain's immune cells), promotes blood-brain barrier dysfunction, and has been linked to cognitive decline and neurodegenerative disease.

The connection between elevated inflammatory markers and increased dementia risk has been established in multiple large cohort studies, adding cognitive preservation to the list of reasons to take inflammaging seriously.

Supporting NAD+ metabolism in the context of inflammation

Understanding the connection between inflammaging and NAD+ depletion opens up new possibilities for intervention. If inflammation drives CD38 expression, and CD38 depletes NAD+, then supporting NAD+ availability may help preserve cellular function under inflammatory stress.

Preclinical research has demonstrated that NAD+ restoration can:

• Improve mitochondrial function despite inflammatory stress
• Enhance sirtuin activity, which has anti-inflammatory effects
• Support DNA repair capacity, reducing damage-induced inflammation
• Preserve metabolic flexibility under stress conditions

While this doesn't eliminate the inflammation itself, it may help maintain cellular resilience when inflammatory stress is present—essentially supporting the "supply side" when demand is elevated.

Can inflammaging be modulated?

The good news is that inflammaging, while progressive, is not entirely inevitable. Multiple evidence-based interventions can modulate inflammatory signaling and potentially slow its progression.

Exercise: the anti-inflammatory intervention

Regular physical activity is one of the most potent anti-inflammatory interventions available. Exercise paradoxically causes acute, transient inflammation (which drives adaptation), but chronically reduces baseline inflammatory markers.

Studies consistently show that regular exercisers have lower IL-6, CRP, and TNF-α levels compared to sedentary individuals. Exercise also improves mitochondrial function, enhances NAD+ biosynthesis, and promotes healthy immune system balance.

Metabolic health and insulin sensitivity

Improving insulin sensitivity through diet, exercise, and metabolic optimization reduces inflammatory signaling throughout the body. The connection is bidirectional—inflammation causes insulin resistance, and insulin resistance worsens inflammation.

Interventions that improve metabolic health—whether caloric restriction, time-restricted eating, or simply maintaining healthy body composition—tend to reduce inflammatory markers as a downstream benefit.

Weight management and visceral fat reduction

Visceral adipose tissue (deep abdominal fat) is metabolically active and highly inflammatory. It secretes pro-inflammatory cytokines directly into circulation, contributing significantly to systemic inflammaging.

Reducing visceral fat through lifestyle modification reduces inflammatory cytokine production at the source, potentially interrupting the inflammation-metabolic dysfunction cycle.

Sleep regulation and circadian health

Sleep disruption rapidly increases inflammatory markers. Even a single night of poor sleep can elevate IL-6 and CRP. Chronic sleep deprivation is associated with sustained elevation of multiple inflammatory cytokines.

Prioritizing consistent, adequate, high-quality sleep represents one of the most accessible anti-inflammatory interventions available.

Stress management and psychological wellbeing

Chronic psychological stress activates inflammatory pathways through multiple mechanisms, including hypothalamic-pituitary-adrenal axis dysregulation and direct effects on immune cell function.

Evidence-based stress reduction—whether through meditation, social connection, therapy, or other approaches—can measurably reduce inflammatory markers.

Is inflammation always harmful?

It's crucial to avoid oversimplifying the role of inflammation in health. Inflammation is not inherently bad—it's essential for survival. Acute inflammation is what allows you to fight infections, heal wounds, and repair damaged tissues.

The inflammation generated during exercise, while technically "pro-inflammatory" in the short term, is precisely what drives beneficial adaptations like muscle growth and mitochondrial biogenesis.

The problem is not inflammation itself. The problem is chronic, unresolved, low-grade inflammation that persists indefinitely without resolution—inflammation that's high enough to cause cellular stress and metabolic dysfunction, but not acute enough to trigger proper resolution mechanisms.

Healthy aging likely requires:

• Robust acute inflammatory responses when genuinely needed
• Effective inflammation resolution pathways that turn off signaling after threats are eliminated
• Low baseline inflammatory tone in the absence of acute challenges
• Maintained metabolic resilience to handle inflammatory stress when it occurs

The goal isn't to eliminate all inflammation—it's to restore the balance between activation and resolution that characterizes healthy, youthful immune function.

What current science does not yet prove

Scientific honesty requires acknowledging the limits of current evidence. While inflammaging correlates strongly with poor aging outcomes, and mechanistic research establishes plausible pathways, several critical questions remain unanswered:

We do not yet have definitive evidence that:

• Reducing IL-6 or other specific cytokines alone extends human healthspan or lifespan
• Targeting CD38 pharmacologically in healthy humans delays biological aging
• NAD+ restoration alone (without addressing underlying inflammatory drivers) reverses inflammaging
• Any single anti-inflammatory intervention produces dramatic longevity benefits in humans

The mechanistic understanding is strong. The correlational evidence is robust. The preclinical data are compelling. But translating these findings into definitive interventions with proven long-term efficacy in diverse human populations requires more research.

This isn't cause for nihilism—the evidence supporting lifestyle interventions like exercise and metabolic health optimization is overwhelming. But it does mean we should maintain appropriate scientific humility about what's proven versus what's plausible.

Final thoughts: a framework for understanding aging

Inflammaging represents a paradigm shift in how we understand biological aging. Rather than viewing aging as simply the passive accumulation of damage, inflammaging reveals aging as an active biological process involving dysregulated immune signaling, altered cellular metabolism, and self-reinforcing feedback loops.

The key insights are:

• Chronic low-grade inflammation develops progressively during aging
• Elevated inflammatory cytokines predict morbidity, frailty, and mortality
• CD38 creates a direct molecular link between inflammation and NAD+ depletion
• NAD+ decline contributes to mitochondrial dysfunction and metabolic aging
• Inflammaging intersects with multiple established hallmarks of aging
• Evidence-based lifestyle interventions can modulate inflammatory signaling

Inflammaging is not simply an immune system issue—it's a systemic biological shift that influences energy metabolism, vascular function, cellular resilience, and tissue integrity throughout the body.

Understanding this framework allows us to approach longevity with scientific clarity rather than simplistic "anti-inflammatory" rhetoric. The goal isn't to eliminate all inflammation indiscriminately, but to restore the balance between activation and resolution, support cellular resilience under inflammatory stress, and address the upstream drivers of chronic inflammation through evidence-based lifestyle optimization.

As research continues to illuminate the molecular mechanisms connecting inflammation to aging, our ability to develop targeted, effective interventions will only improve. But even with current knowledge, a comprehensive approach addressing metabolic health, physical activity, sleep quality, stress management, and cellular NAD+ support represents the most scientifically grounded strategy for modulating inflammaging and supporting healthy longevity.

References

1. Franceschi, C., Bonafè, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E., & De Benedictis, G. (2000). Inflamm-aging: an evolutionary perspective on immunosenescence. Annals of the New York Academy of Sciences, 908(1), 244-254. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x
2. Ferrucci, L., & Fabbri, E. (2018). Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nature Reviews Cardiology, 15(9), 505-522. https://doi.org/10.1038/s41569-018-0064-2
3. Camacho-Pereira, J., Tarragó, M. G., Chini, C. C., Nin, V., Escande, C., Warner, G. M., ... & Chini, E. N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metabolism, 23(6), 1127-1139. https://doi.org/10.1016/j.cmet.2016.05.006
4. Gomes, A. P., Price, N. L., Ling, A. J., Moslehi, J. J., Montgomery, M. K., Rajman, L., ... & Sinclair, D. A. (2013). Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155(7), 1624-1638. https://doi.org/10.1016/j.cell.2013.11.037
5. Campisi, J. (2013). Aging, cellular senescence, and cancer. Annual Review of Physiology, 75, 685-705. https://doi.org/10.1146/annurev-physiol-030212-183653
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7. Ridker, P. M., Hennekens, C. H., Buring, J. E., & Rifai, N. (2000). C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New England Journal of Medicine, 342(12), 836-843. https://doi.org/10.1056/NEJM200003233421202