Inflammaging from a Population View

In a landmark study published in Nature Aging on July 7, 2025, researchers challenge a cornerstone of modern gerontology by showing that inflammaging, chronic, age-associated low-grade inflammation, is not universal across all human populations. The abstract states the following: "Inflammaging, an age-associated increase in chronic inflammation, is considered a hallmark of aging. However, there is no consensus approach to measuring inflammaging based on circulating cytokines. Here we assessed whether an inflammaging axis detected in the Italian InCHIANTI dataset comprising 19 cytokines could be generalized to a different industrialized population (Singapore Longitudinal Aging Study) or to two indigenous, nonindustrialized populations: the Tsimane from the Bolivian Amazon and the Orang Asli from Peninsular Malaysia.

We assessed cytokine axis structure similarity and whether the inflammaging axis replicating the InCHIANTI result increased with age or was associated with health outcomes. The Singapore Longitudinal Aging Study was similar to InCHIANTI except for IL-6 and IL-1RA. The Tsimane and Orang Asli showed markedly different axis structures with little to no association with age and no association with age-related diseases. 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." (Franck et. al. 2025)

The research team analyzed 19 cytokines in over 2,800 individuals from four diverse populations: two industrialized cohorts: Italy's InCHIANTI and the Singapore Longitudinal Aging Study (SLAS); two non-industrialized, Indigenous groups: the Tsimane of the Bolivian Amazon and the Orang Asli of Peninsular Malaysia.

 

In Italy and Singapore, the industrialized regions noted classic inflammaging signatures with inflammatory markers like IL‑6, TNF-α, and CRP increased with age, and correlated strongly with age-related chronic diseases such as cardiovascular and kidney disease.

In contrast, the Tsimane People and Orang Asli did not show a consistent rise in these markers with age. Their inflammatory profiles were distinctive and driven largely by infection, which they chronically battle, not chronological aging. There inflammation markers did not predict chronic disease risk. As has been discussed in previous newsletters regarding the Tsimane and ASCVD, these findings suggest that the inflammaging observed in Western populations may be largely a byproduct of industrial lifestyles characterized primarily by sedentary behavior, ultra processed calorie dense diets, low natural microbial exposure, chemical exposure/bioaccumulation and genetic/environment mismatches.

Key findings:

1.  Biomarkers of inflammation validated in Industrial populations do not translate globally to environmentally diverse peoples. Epidemiological markers such as IL‑6 or CRP should be interpreted with population context in mind.

2.  Interventions aimed at reducing inflammaging: diet, toxin avoidance, exercise, microbial exposure and more will need customization to environmental and cultural realities. Think the Stein NEJM paper regarding the Amish Peoples in the US and Asthma. Yes and industrialized country but not the enclave where the individuals live. Interventions efficacious in industrialized settings might not apply in traditional-lifestyle groups.

3.  This study reinforces the concept of an evolutionary mismatch between human immune systems adapted to ancestral environments with profound infectious burdens and limited toxin exposure versus modern contexts, driving chronic inflammation in industrialized societies.

 

The work by Franck et al. fundamentally reframes inflammaging as a context-dependent phenomenon, not a universal hallmark of biological aging. Aging with inflammation appears to be contextual and modifiable, influenced by diet, activity, toxin avoidance, microbial ecology, and environmental exposures suggesting pathways for prevention and resilience beyond chronological aging alone.

This research underscores the importance of inclusive, globally representative aging studies, and calls for more nuanced biomarkers and interventions that respect the full spectrum of human environments and lifestyles. As always, there is no one size fits all reality.

Dr. M

Franck Nature Aging

Terekhova Nature Aging