Rethinking a Hallmark of Aging: Inflammaging May Be Lifestyle, Not Biology
Indigenous populations with high infection rates don't develop age-related chronic inflammation
Researchers have been trying to understand the processes that cause aging at a cellular level and at an organismal level for a long time.
To understand aging, it needs to be defined. In 2013, there was a proposal of 9 “hallmarks” of aging, including DNA damage, telomere shortening, and more.
These hallmarks are a scientific framework that identifies the key biological processes that drive aging. In 2023, the hallmarks were updated to 13 and now include inflammaging as a cause of aging. The idea of the hallmarks of aging framework is that these 13 biological processes cause aging — and that altering the processes should reverse aging.
New study, casting doubts on a ‘hallmark’ of aging:
There’s a new study out that casts doubt on whether inflammaging - chronic inflammation in old age — is actually a cause of aging. The study, titled Nonuniversality of inflammaging across human populations, was published in the journal nature aging in 2025.
Researchers compared inflammatory markers (cytokines) in blood samples from four populations:
Two industrialized populations, InCHIANTI (Italy) and SLAS (Singapore Longitudinal Aging Study).
Two indigenous, nonindustrialized populations, Tsimane (Bolivian Amazon) and Orang Asli (Malaysia).
Chronic inflammation in industrialized populations:
The researchers found that the Italian and Singapore (industrialized) populations fit the profile of chronic inflammation that increased with age. They looked at CRP, IL-6, TNF, sTNF-RI, sTNF-RII as the inflammatory markers, and they found that there was a strong association with the chronic diseases of aging, such as kidney disease, diabetes, and heart disease. The results were fairly similar between Italy and Singapore.
No inflammaging in indigenous populations:
When the researchers looked at and normalized the data across other population groups, a pattern emerged. The non-industrialized, indigenous population groups from the Bolivian Amazon (Tsimane people) and Malaysia (Orang Asli group), had little to no increase in the inflammatory markers with age and no association with chronic disease.
However, these indigenous populations had high levels of specific inflammatory cytokines due to frequent infections.
The researchers found that 40-80% of the indigenous populations had parasitic worms. Fungal infections, respiratory infections, and gastrointestinal infections were also common.
So CRP may be high, but that didn’t correlate with IL-6 or TNF. Different cytokines were active depending on specific infections, and none of them seemed to drive inflammaging.
What this means…
The study suggests that inflammaging is not universal biology, not inevitable, but rather a consequence of industrialized lifestyles (diet, pollution, sedentary behavior, etc.). There’s also an evolutionary mismatch between our modern environment and our immune systems. We may be built for periodic worms.
Why does this matter?
The hallmarks of aging are a framework, a foundation for a lot of new research on reversing aging. It’s important that they are understood and correct as far as causality, and the findings from industrialized populations may not be universal.
The indigenous population data show that high inflammation is not always harmful inflammation. Infection-driven inflammation is different from metabolic, lifestyle, or environment-driven inflammation. Even at an older age, the immune system can have high activity without triggering chronic diseases of inflammation.
This study highlights that evolution shaped immunity for high-pathogen environments, not modern sterile ones. It concludes: “Inflammaging, as measured in this manner in these cohorts, thus appears to be largely a byproduct of industrialized lifestyles, with major variation across environments and populations.”
Making connections and changing my perspective:
I’ve written a lot in the past about tamping down chronic inflammation in aging. If elevated inflammatory cytokines aren’t a biological process that is part of aging, then the focus should be on preventing the cause of inflammation rather than taking supplements that suppress certain cytokines.
My article on T cell exhaustion in cancer immunotherapy being exacerbated by sucralose consumption is a perfect example…
You want a strong, continuing immune response to fight cancer (most types of cancer, anyway). Immunotherapy drugs help boost the T cell response to the tumor. That’s great, until the T cells become exhausted and stop responding. Researchers recently found that l-arginine is a key amino acid for T cell metabolism, and that sucralose consumption changed the gut microbiome in a way that decreased l-arginine production. This represents a modern, industrialized lifestyle change (sucralose consumption) that limits the power of your immune response to cancer.
A lot of things in our modern environment - microplastics, pesticides, phthalates, PFAS, artificial sweeteners, food additives, antibiotics, dishwashing detergent - alter our gut microbiome. And the gut microbiome composition is integral to the balance of our immune response throughout the body.
Tamping down chronic inflammation is likely still important to reducing chronic diseases, like heart disease, diabetes, and arthritis. But balancing that with a robust immune response is also important. The resolution of inflammation as an active process that relies on pro-resolving mediators is likely a key component. The omega-3s, DHA and EPA, are necessary for the synthesis of pro-resolving mediators.
In the end, chronic inflammation may be aging us in modern societies, but it’s not an inevitable biological process—it’s largely shaped by how we live and what we are exposed to.
The hallmarks framework implicitly treats aging as a trajectory toward dysfunction. A different perspective is that aging primarily narrows the range within which systems can operate safely and recover, without requiring chronic damage or loss of regulation. That distinction matters if we want to define healthy aging rather than pathological aging. How we define aging determines whether interventions aim to sustain capacity or merely manage decline.
So, can you tell me, what are the hallmarks of healthy aging?
Such an important reframing! Clinically, we often talk about “inflammaging” as if it’s an inevitable, hard-wired feature of getting older, but the cross-population signal you highlight suggests something more actionable: a large component of late-life chronic inflammation may be an exposure phenotype of industrialization, not a universal biologic destiny. 
Two nuances I especially appreciated:
1. Not all inflammation is the same. Infection-driven cytokine activity can be high without tracking with cardiometabolic disease, whereas the “sterile” inflammatory pattern in industrialized cohorts correlates with diabetes, CKD, and CVD. That distinction matters for how we counsel patients; “lower inflammation at all costs” can backfire if it blunts immune competence. 
2. The implied clinical pivot is smart: instead of chasing cytokines with a supplement stack, focus on upstream drivers that plausibly create sterile inflammation (visceral adiposity/insulin resistance, ultraprocessed diet signals, sleep/circadian disruption, inactivity, pollutants, microbiome-disruptors) and on resolution biology (repair and pro-resolving pathways), not just suppression. 
If we’re going to talk about “hallmarks”, this paper nudges us toward a parallel framework for healthy aging: preserved metabolic flexibility, robust immune responsiveness with good resolution, and physiologic reserve. Great post, evidence-based, but also genuinely hopeful because it points to levers we can actually pull.