Have you heard of Inflammaging? It tells us that with aging, long-term, low-grade chronic inflammation in the body is the hidden culprit behind aging and various age-related diseases (such as heart disease, diabetes, and Alzheimer’s disease). Based on this, we’ve formed a common belief: anti-aging, to a large extent, is a battle against inflammation.
However, a newly published study in Nature Aging has raised a sharp question about this universal truth: If Inflammaging is widespread, why is it barely detectable in some middle-aged and elderly populations[1]?
This article will take you through the rise of Inflammaging and delve into this new finding that may rewrite textbooks.
01 How Did Inflammaging Become a Top Anti-Aging Concept?
In 2000, Italian scholar Claudio Franceschi first proposed the concept of Inflammaging (inflammatory aging)[2].
He observed that the older we get, the more likely we are to enter a state of chronic, low-grade inflammation. He believed this was an evolutionary trade-off: in youth, a "strong" inflammatory response protects us, but in old age, this persistent mild inflammation becomes a spark that ignites various age-related diseases, threatening health.
Figure note: With increasing age, inflammation remains persistently activated at low levels, leading to Inflammaging
This profound insight quickly became a research hotspot. Over the next two decades, scientists added key pieces to refine this theory:
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Senescent cells continuously secrete a complex set of pro-inflammatory molecules called SASP (Senescence-Associated Secretory Phenotype), which is considered the direct driver of Inflammaging[3].
Figure note: Scroll up/down to view senescent cells (brown nuclei) secreting SASP factors, inducing senescence (blue nuclei) or canceration (red nuclei) in neighboring cells, forming an inflammation amplification loop
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Numerous studies have confirmed that this systemic inflammation is closely linked to almost all major age-related diseases (e.g., Alzheimer’s disease, atherosclerosis, metabolic disorders)[4]. It can be said that Inflammaging has become a key theory explaining the age-old question of "why people are prone to multiple diseases as they age."
Figure note: Inflammation accelerates the progression of most diseases -
Based on the above understanding, "anti-inflammation" has become one of the core anti-aging strategies. Whether it’s drugs with anti-inflammatory potential (such as rapamycin), senolytic therapies targeting senescent cells, or lifestyle interventions (such as calorie restriction and regular exercise), their anti-aging mechanisms are closely related to inhibiting inflammation or eliminating its sources.
With the support of massive evidence, chronic inflammation was officially listed as one of the "12 Hallmarks of Aging" by Cell in 2023[5], completing the transition from a hypothesis to a core doctrine.
Figure note: The 12 Hallmarks of Aging, including chronic inflammation, alongside other hallmarks such as genomic instability, telomere attrition, and cellular senescence
But is this rule we hold as sacred applicable to every person on Earth? Or is the Inflammaging we know a universal law of human aging, or just a product of specific environments?
02 A Contradictory New Study?
To answer this question, scientists selected four groups of people (nearly 3,000 individuals) with completely different living environments and lifestyles, dividing them into two camps:
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Industrialized society group: Including cohorts from Italy and Singapore. They represent the lifestyle of most of us—urbanized, good sanitation conditions, and a diet high in processed foods.
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Non-industrialized society group: This group has more "primitive" lifestyles, including the Tsimane people in the Bolivian Amazon rainforest and the Orang Asli people in Malaysia. They still retain ancestral lifestyles—hunting, gathering, and farming—with high physical activity and higher infection risks.
The results showed that in industrialized populations (Italian and Singaporean cohorts), the Inflammaging score (a measure of inflammatory aging levels) increased with age. Moreover, this increase in inflammation was closely linked to the risk of multiple age-related chronic diseases. For example, each unit increase in the Inflammaging score was associated with a 4.75- to 5.75-fold higher risk of chronic kidney disease.
Figure note (left): Relationship between Inflammaging score and age (red and blue lines); Figure note (right): Association between Inflammaging score and disease risk (industrialized populations)
This perfectly confirms the classic textbook theory: Inflammaging is an important driver of age-related diseases.
However, in the Tsimane and Orang Asli populations, the picture changed dramatically: the Inflammaging score was almost a horizontal line—showing no upward trend with age.
Figure note: Relationship between Inflammaging score and age (green and purple lines)
Looking at their overall inflammation levels: although generally higher, they seemed decoupled from the age-related diseases we know. There was no significant association between Inflammaging scores and hypertension, diabetes, or even chronic kidney disease. Additionally, the Tsimane people are known to have the healthiest blood vessels in the world—an 80-year-old Tsimane person has a vascular age equivalent to that of a 55-year-old American[6].
Figure note (left): Association between Inflammaging score and disease risk (Tsimane vs. Italian populations); Figure note (right): Association between Inflammaging score and disease risk (Orang Asli vs. Italian populations)
The comparison of these two sets of data ultimately leads to a conclusion: The Inflammaging we currently define does not seem to be an inherent fate of human aging… If Inflammaging is not inevitable, then what exactly is it?
03 The Paradox of "Dirty" vs. "Clean" Environments
To answer this question, scientists proposed the Evolutionary Mismatch hypothesis: Our modern immune system is a product of millions of years of evolution. It is highly trained to deal with threats our ancestors constantly faced—infectious inflammation caused by external invaders such as bacteria and viruses.
Take indigenous populations as an example: Although they bear a high inflammatory burden due to long-term exposure to various pathogens, they are largely exempt from modern diseases of civilization like heart disease and diabetes. This does not mean inflammation is harmless to them, but rather that the inflammation in their bodies is the type their immune systems recognize and can handle.
Figure note: Unlike industrialized populations (InCHIANTI cohort), the association network of inflammatory factors in the Tsimane people (THLHP cohort) is loose and disorganized
In modern times, however, our immune systems face new challenges: The threat of persistent infections has decreased significantly, replaced by new, sterile pro-inflammatory factors: high-sugar, high-fat "comfort foods," sedentary lifestyles glued to chairs, and overwhelming mental stress… (The immune system thinks: "I’ve never seen these before!")
Faced with these unfamiliar "enemies," the "CPU" of our ancient immune system is overwhelmed. It does not know how to handle this non-infectious, persistent low-grade stimulation, so it mistakenly activates defense programs. The result is the highly coordinated and persistent Inflammaging axis we observe—ultimately causing long-term, harmful effects on the body.
Figure note (top): Core inflammatory factors in industrialized populations are highly coordinated; Figure note (bottom): The correlation between core inflammatory factors in non-industrialized populations is disrupted
This is the core of Inflammaging: It is not an inevitable phenomenon of aging. Instead, it should be seen as a "system incompatibility" response of our bodies (shaped by millions of years of evolution) to modern lifestyles—one that ultimately leads to harmful consequences.
…If chronic inflammation is not a standard part of aging, can it still retain its title as a "core hallmark of aging"?
04 Should Inflammaging Remain Among the 12 Hallmarks of Aging?
Don’t jump to conclusions yet! To answer this question, we first need to clarify the criteria: Only phenomena that universally occur during normal aging qualify as core hallmarks of aging.
Clearly, the findings of this study directly conflict with this golden standard. A phenomenon considered a core hallmark fails to show its classic pathogenic pattern in the natural aging of two human populations—undoubtedly shaking its status. So… how can we explain this?
No. 1 Downgrade / Add a Caveat
First, follow the rules strictly. The conclusion seems obvious: Chronic inflammation—at least in the form we currently define—should no longer occupy a spot as a "core hallmark of human aging." Instead, it is more like a unique hallmark of industrial aging or environmentally mismatched aging.
If we don’t want to "delete" it outright… we can also add a caveat to the aging hallmark: Chronic inflammation (its systemic manifestations and harmfulness are highly dependent on environment and lifestyle).
No. 2 Shift Perspective
Alternatively, the problem may not lie with the hallmark of chronic inflammation itself, but with our definition of it. The hallmark defined in Cell may refer to a more fundamental, cellular-molecular process (the emergence of senescent cells and SASP secretion)—a "fire source" of aging that remains universal.
Returning to this study: What it measured was a systemic inflammatory network composed of multiple cytokines in the blood. This is like how a fire source produces different types of smoke in different environments: In modern society, it produces harmful dense smoke (coordinated, pathogenic inflammation); in natural environments, it may produce harmless light smoke (loose, non-pathogenic inflammation).
Following this line of thinking, the hallmark itself is not wrong—but its manifestations and harmfulness are environment-dependent.
Finally, one last question: Is our long-standing "anti-inflammatory anti-aging strategy" still effective?
Of course it is! After all, most of us are the main victims of Inflammaging—a "disease of industrialization." Therefore, all strategies aimed at reducing chronic inflammation induced by modern lifestyles (high-sugar diets, sedentary behavior, stress) are necessary—whether it’s anti-inflammatory diets, regular exercise, or scientific supplement use, they are all worth persisting with.
The simple, authentic daily lives of the Tsimane and Orang Asli people once again confirm this basic truth: A healthy diet, sufficient exercise, and a positive mindset are the cornerstones of healthy longevity.
References
[1] https://doi.org/10.1038/s43587-025-00888-0
[2] 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, 244–254. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x
[3] Young, A. R. J., & Narita, M. (2009). SASP reflects senescence. EMBO Reports, 10(3), 228.
[4] Lee, D., Lee, V. M., & Hur, S. K. (2022). Manipulation of the diet-microbiota-brain axis in Alzheimer's disease. Frontiers in Neuroscience, 16, 1042865. https://doi.org/10.3389/fnins.2022.1042865
[5] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278. doi: 10.1016/j.cell.2022.11.001
[6] Kaplan, H., Thompson, R. C., Trumble, B. C., Wann, L. S., Allam, A. H., Beheim, B., Frohlich, B., Sutherland, M. L., Sutherland, J. D., Stieglitz, J., Rodriguez, D. E., Michalik, D. E., Rowan, C. J., Lombardi, G. P., Bedi, R., Garcia, A. R., Min, J. K., Narula, J., Finch, C. E., Gurven, M., … Thomas, G. S. (2017). Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. The Lancet, 389(10080), 1730–1739. https://doi.org/10.1016/S0140-6736(17)30752-3
[2] 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, 244–254. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x
[3] Young, A. R. J., & Narita, M. (2009). SASP reflects senescence. EMBO Reports, 10(3), 228.
[4] Lee, D., Lee, V. M., & Hur, S. K. (2022). Manipulation of the diet-microbiota-brain axis in Alzheimer's disease. Frontiers in Neuroscience, 16, 1042865. https://doi.org/10.3389/fnins.2022.1042865
[5] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278. doi: 10.1016/j.cell.2022.11.001
[6] Kaplan, H., Thompson, R. C., Trumble, B. C., Wann, L. S., Allam, A. H., Beheim, B., Frohlich, B., Sutherland, M. L., Sutherland, J. D., Stieglitz, J., Rodriguez, D. E., Michalik, D. E., Rowan, C. J., Lombardi, G. P., Bedi, R., Garcia, A. R., Min, J. K., Narula, J., Finch, C. E., Gurven, M., … Thomas, G. S. (2017). Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. The Lancet, 389(10080), 1730–1739. https://doi.org/10.1016/S0140-6736(17)30752-3