How Protected Red Blood Cell Health = Protection Against Frailty

Healthy Aging

Where A Younger Biological Age May Very Well All Start: Hello, Red Blood Cells

A few weeks back, we covered a metabolic storm that has been brewing for decades. In this series, we’re sharing the science behind the earliest igniters of metabolic dysfunction. Just as importantly, we’ll discuss studies supporting how we can take back control of our long-term health. In the last issue, we shared how this storm can start with fragile cells. This week, we talk about how protecting the integrity of our red blood cells can protect us against whole-body frailty.

I’m in. Give me the 411 on RBCs.

Red blood cells (aka RBCs) are special for oh so many reasons. They circulate throughout our body. They deliver oxygen to all of our tissues (including you, brain). They regulate iron. And they are readily accessible to provide insights not only on the health of our RBCs, but our whole-body cellular health.

When you get a routine blood test, chances are your doctor will include the following red blood cell measurements:

• RBC count. You got it – this is the number of red blood cells in a given amount of blood.
• Hematocrit. This is the % of total blood volume that is red blood cells.
• Hemoglobin. This measures the iron-rich protein in your RBCs that carries oxygen from your lungs to your body. Low hemoglobin is the primary biomarker of anemia.
• MCV (mean corpuscular volume). This measurement is the average size of your RBCs, where low MCV = small cells and high MCV = large cells.
• MCH (mean corpuscular hemoglobin). This measurement is the average amount of hemoglobin in a single red blood cell.
• MCHC (mean corpuscular hemoglobin concentration). This measurement is the average amount of hemoglobin in your cells relative to the cell size. Low MCHC can be an indicator of iron deficiency.
• RDW (red blood cell distribution width). RDW measures the amount of variation in your red blood cell size. The higher the RDW, the more variable the size of your red blood cells.

How these different biomarkers play out on your blood test help to determine if your RBCs are healthy. And (importantly) if they’re not healthy… why.

How these RBC measurements change with age.

As we shared a couple of weeks back, our cell membranes become more fragile as we get older. This includes our RBCs. In a study with 200 healthy volunteers aged between 20 and 65 years old, Kumar found that increasing age was indeed associated with the following:

• Decreasing hemoglobin
• Increasing osmotic fragility (a measure of how quickly RBCs pop when exposed to increasingly salty water)
• Increasing lipid peroxidation

Side note: If you recall from our last issue, increased cell fragility and lipid peroxidation are also components of a newly discovered form of cell death, ferroptosis. But we’ll get to that connection next week.

Lower hemoglobin with aging is so common that – for a long time – lower hemoglobin was considered normal for older folks. We now know that lower hemoglobin (aka, poor RBC health) is not normal… no matter your age.

Why we care about RBC health with age.

In their review, Guralnik et al. summarize the prevalence of low hemoglobin among people who are 60 years and older. Specifically, they report that:

• As many as 15% of people 60 years or older are anemic.
• Anemia is associated with higher risks of death, all-cause hospitalizations, poor functional capacity, lower quality of life and depression.
• 40% of older people with anemia of aging have unexplained anemia.

They conclude that “…because even mild anemia is strongly linked to poor clinical outcomes, it should receive clinical attention rather than simply being considered a normal part of aging.”

The big reveal: RDW as an indicator of fragile RBCs (and biological aging, too).

So, the question is… what is causing unexplained lower hemoglobin with age? Well, we already shared above that Kumar showed our red blood cells become more fragile with age. 

Ends up, one of the most important emerging indicators of fragile red blood cells is red blood cell distribution width (RDW). This makes a lot of sense, right?

• The more fragile our red blood cells, the quicker they break down.
• The quicker they break down, the more new RBCs we have to make.
• The result: a greater overall variation in RBC size…which is reflected in higher RDW

Lippi et al. demonstrated that RDW significantly increased as people aged from 50 to 90 years. Further, Kim et al. showed that people with higher RDW were “weaker, walked more slowly, had worse cognitive function… and were more likely to become frail”. They proposed RDW as a marker for biological aging.

They weren’t wrong. In a hallmark paper published in Aging, Levine et al. found that, among nine clinically meaningful and significant predictors of biological age, RDW was the strongest predictor. The higher one’s RDW, the older their biological age. Levine’s equation is better known today as AgeAccelPheno – considered by many as the gold standard of determining our biological age (aka, a biological clock).

To summarize, keeping our RBCs from becoming frail translates into protecting us from becoming frail. A main measurement to watch? Red blood cell distribution width (aka RDW).