A Simple But Powerful Predictor of Longer Life

Healthy Aging

Let’s talk HRR (a biomarker of resilience)

There has been increasing interest in the role of both hemoglobin and red blood cell distribution width (aka RDW) as key biomarkers of long-term health. A recent paper published in Nature’s Scientific Reports conducted a massive study into just how well hemoglobin, RDW and a combined biomarker called HRR predicted an individual person’s healthy lifespan. As well as how, as a population, we’re doing on that lifespan front. Let’s dive in.

But first, what are hemoglobin, RDW and HRR?

Well, that’s a great place to start.

• Hemoglobin is a protein in red blood cells that carries and delivers oxygen to our tissue. Hemoglobin is routinely measured during lab checkups, and low hemoglobin levels are used  to identify people with anemia. In general, we want to have healthier, higher hemoglobin levels. Unfortunately, as described by Wacka et al., our hemoglobin levels tend to decline as we age.
• Red blood cell distribution width (RDW) measures how much variability there is in  red blood cell volume and size. People with high RDW have unstable red blood cells. In general, we want  to have lower RDW.  This is because, as described by Yadav et al., many studies have linked lower RDW to better long-term health. And as you can see in the figure below, those studies have been increasing.
• The hemoglobin-to-RDW ratio (HRR) is an emerging predictor of numerous long-term health outcomes. Specifically, higher HRR is good, and lower HRR is bad. Which makes sense, given what you now know about hemoglobin and RDW.

So, to summarize, we typically want higher hemoglobin, lower RDW and higher HRR.

How did this latest study look at potential predictors of longer life?

Lai et al. looked at a cohort of 28,825 participants from the U.S. National Health and Nutrition Examination Survey (1999-2018) to evaluate how well HRR predicted mortality. They used robust statistical models, including:

• Weighted Cox regressions
• Restricted cubic spline models
• Subgroup and sensitivity analyses
• Trend tests for temporal trends
• Fully adjusted models controlling for potential confounding factors

By doing so, this study was able to not only determine associations between HRR and mortality, but predicted causality.

Got it. So, what did they find?

There were two key findings:

First, as expected, higher HRR was linked to lower risks of mortality from any cause, as well as the two leading causes of death: cancer and cardiovascular disease. Specifically, people who had the absolute highest HRR were the healthiest and most protected compared to those who had the lowest HRR.

Second, there was a concerning trend of decreasing HRR in the U.S. population over time. This trend of decreasing HRR coincides with the increase in aging-associated conditions among younger people, especially among those born since the 1990s and are now in their 30s.

The bottom line: The Lai et al. study adds to the growing body of evidence that HRR is an easy-to-measure biomarker of individuals’ lifespan potential, and that interventions to protect a higher HRR could support our long-term health – for both individuals and global populations.

But is there an explanation for how higher HRR causes longer life?

Wonderfully, yes.

• As we age, our cell membranes – including our red blood cells – become more fragile. This fragility is due to cells’ increased susceptibility to attack by oxygen (aka lipid peroxidation).
• A.J. Hulbert showed that cell membranes with more polyunsaturated fatty acids are more fragile and susceptible to peroxidation due to multiple double bonds in their structure. In fact, he showed that the more stable the fatty acids in the cell membrane (aka the fewer the double bonds), the longer was a species’ lifespan.
• In 2012, Dixon et al. discovered an entirely new form of cell death called ferroptosis, which is caused by – yes – fragile fatty acids in cell membranes. The result? Higher lipid peroxidation, accelerated aging, and impaired metabolic, liver, heart, immune and cognitive function.

As such, strengthening cell membranes against lipid peroxidation – including stabilizing red blood cell membranes – will result in healthier, higher hemoglobin, higher HRR, and lower RDW.  This protective function also supports core cells throughout our body, translating to long-term health. Less fragility, more stability.