Metabolic health status and aging determined by inflammation, not weight

Metabolic health is not reliably determined by weight or BMI (body mass index). Lean individuals can suffer from cardiovascular and other diseases involving metabolism, and  evidence has been mounting that supports the notion of a subtype of obesity that is metabolically healthy. A study recently published in JCEM (The Journal of Clinical Endocrinology & Metabolism) shows that inflammation can determine metabolic health in both obese and non-obese populations. The authors state:

"Inflammation is a potential mechanism linking obesity and cardiometabolic risk... The aim of the study was to investigate the extent to which differences between metabolically healthy and unhealthy obese and nonobese adults, defined using a range of metabolic health definitions, are correlated with a range of inflammatory markers."

To do so they measured serum acute-phase reactants, adipocytokines, proinflammatory cytokines, and white blood cell counts in 2047 men and women who they classified as obese (BMI more than 30 kg/m2) and nonobese (BMI less than kg/m2). They established metabolic health status with five definitions that included markers such as blood pressure, triglycerides, LDL, HDL, total cholesterol, fasting glucose, and insulin resistance (HOMA). Several of the inflammatory markers were more strongly associated with metabolic health:

"According to most definitions, metabolically healthy obese and nonobese individuals presented with lower concentrations of complement component 3, C-reactive protein, TNF-α, IL-6, and plasminogen activator inhibitor-1; higher adiponectin levels; and reduced white blood cell count compared to their metabolically unhealthy counterparts. Logistic regression analysis identified greater likelihood of metabolically healthy obesity among individuals with lower levels of complement component 3 (odds ratios [ORs], 2–3.5), IL-6 (ORs, 1.7–2.9), plasminogen activator inhibitor-1 (ORs, 1.7–2.9), and white blood cells (ORs, 2.1–2.5) and higher adiponectin concentrations (ORs, 2.6–4.0)."

In other words, lower C3, CRP, TNF-α, IL-6, PAI-1, and white blood cells, along with higher adiponectin were associated with metabolic health in both groups. Lower C3, IL-6, PAI-1 and higher adiponectin were most strongly indicative of metabolic health among the obese. The authors' conclusion highlights what clinicians should bear in mind:

"Favorable inflammatory status is positively associated with metabolic health in obese and nonobese individuals. These findings are of public health and clinical significance in terms of screening and stratification based on metabolic health phenotype to identify those at greatest cardiometabolic risk for whom appropriate therapeutic or intervention strategies should be developed. "

 Furthermore, inflammation is turning out to be a key determinant of the quality of aging. The authors of a paper recently published in CMAJ (Canadian Medical Association Journal) state:

"Chronic inflammation has been implicated in the pathogenesis of age-related conditions, such as type 2 diabetes, cardiovascular disease, cognitive impairment and brain atrophy... For example, obesity increases inflammation, and chronic inflammation, in turn, contributes to the development of type 2 diabetes by inducing insulin resistance, and to coronary artery disease by promoting atherogenesis. Thus, raised levels of inflammation appear to be implicated in various pathological processes leading to diseases in older age... We assessed inflammatory markers twice over a 5-year exposure period to examine the association between chronic inflammation and future aging phenotypes in a large population of men and women."

They examined interleukin-6 (IL-6) levels for 3044 middle-aged adults at baseline and 5 years earlier and correlated it with cause-specific mortality, chronic disease and functioning from hospital and register data and clinical examinations. The authors focused on IL-6 because:"Of the various markers of systemic inflammation, interleukin-6 is particularly relevant to aging outcomes. There is increasing evidence that interleukin-6 is the pro-inflammatory cytokine that “drives” downstream inflammatory markers, such as C-reactive protein and fibrinogen. Interleukin-6, in contrast to C-reactive protein and fibrinogen, is also likely to play a causal role in aging owing to its direct effects on the brain and skeletal muscles. In addition, results of Mendelian randomization studies of interleukin-6 and studies of antagonists are consistent with a causal role for interleukin-6 in relation to coronary artery disease, again in contrast to C-reactive protein and fibrinogen."They created four aging phenotypes at the 10-year follow-up defined as:

• Successful aging (free of major chronic disease and with optimal physical, mental and cognitive functioning)
• Incident fatal or nonfatal cardiovascular disease
• Death from noncardiovascular causes
• Normal aging (all other participants)

Chronic inflammation as determined by higher IL-6 levels was clearly associated with the poorer aging phenotypes:

"Of the 3044 participants, 721 (23.7%) met the criteria for successful aging at the 10-year follow-up, 321 (10.6%) had cardiovascular disease events, 147 (4.8%) died from noncardiovascular causes, and the remaining 1855 (60.9%) were included in the normal aging phenotype. After adjustment for potential confounders, having a high interleukin-6 level (> 2.0 ng/L) twice over the 5-year exposure period nearly halved the odds of successful aging at the 10-year follow-up (odds ratio [OR] 0.53) and increased the risk of future cardiovascular events (OR 1.64) and noncardiovascular death (OR 2.43)."

IL-6 is not the only useful metric for chronic inflammation in aging, but the authors interpret their data as offering good evidence for its use:

"Chronic inflammation, as ascertained by repeat measurements, was associated with a range of unhealthy aging phenotypes and a decreased likelihood of successful aging. Our results suggest that assessing long-term chronic inflammation by repeat measurement of interleukin-6 has the potential to guide clinical practice.

And, not surprisingly, two measurements of IL-6 were better than one:

"Our results on the associations between inflammation, cardiovascular events and death from noncardiovascular causes are concordant with those reported in the literature. However, our results also show that measuring chronic inflammation twice may be a better predictor of future cardiovascular disease and noncardiovascular death than measuring inflammation only once."

In conclusion:

"We found that chronic inflammation characterized by a high interleukin-6 level (> 2.0 ng/L) measured twice over the 5-year exposure period nearly halved the odds of successful aging after 10 years of follow-up compared with maintaining a low level of interleukin-6 (< 1.0 ng/L twice over the exposure period). Our study showed that high interleukin-6 levels at baseline were inversely associated with most of the individual components that characterize successful aging..."

 In this context it's important to consider the role of autoimmunity in inflammation that produces poor aging outcomes. A paper just published in Experimental Gerontology shows how an increase in the Th17/Treg ratio, a pro-inflammatory shift that is a hallmark of autoimmune phenomena, is also associated with increased inflammation of aging called 'inflammaging'.

"Aging is associated with multiple changes in the proliferative and functional abilities of the immune system which are not related to any pathology but consequences in immunosenescence and inflammaging... T helper (TH) 17 cells have been implicated in the development of autoimmune and chronic inflammatory diseases in humans. Additionally, a reciprocal relationship between these pro-inflammatory TH17 and the anti-inflammatory regulatory T cells (Tregs) has been described."

The authors investigated the proportion of pro-inflammatory TH17 cells (CD4 + IL23R +) and anti-inflammatory Tregs (regulatory T cells that modulate the immune response and depend on vitamin D) along with their respective cytokines IL-17 and IL-10 in human healthy donors:

"The data revealed a continual increase of basal CD4 + IL23R + cell amounts in the different age groups. By analyzing the balance of both T-cell subsets it was observed that, on a basal resting level, TH17 cells were significantly increased in older individuals whereas Tregs were reduced."

Clinical note: This is of great practical significance since almost all the manifold disorders associated with aging, from diminished cognitive function to osteoporosis, have an inflammatory component. The authors conclude:

"...changes of the TH17/Treg ratios in combination with altered cytokine expression during aging may contribute to an imbalance between the pro-inflammatory and the anti-inflammatory immune response. This indicates a higher susceptibility to develop inflammatory diseases with increasing age."