Core Biomarkers of High-Functioning Agers

Healthy Aging

Red Blood Cell Strength = Whole Body Strength

When we think about getting older, one of our greatest fears is frailty. But what causes frailty? This week, we cover a newly published longitudinal study from Stanojevic et al., which is looking at how ferroptosis, disrupted iron handling, and impaired mitochondrial health may drive frailty – which then gives us something to target to protect our long-term health, longer. Let’s dive in.

What exactly is frailty?

Good question. As described by O’Neill et al. and Anton et al., frailty can be defined as declining physical function that results in loss of independence and increased susceptibility to falls, longer hospital stays, and mortality.

In the Stanojevic et al. study, they focused on a handful of physical function measurements among 114 adults (average age of 75.8 years). Measurements included the following:

• Short Physical Performance Battery (SPPB, which measures gait speed over a 4-meter walk, lower body strength using a repeated chair stand test, and a balance test)
• 6-minute walk distance
• Handgrip strength
• Knee extensor torque

They specifically used the SPPB scores to define people who were High Functioning (HF = SPPB score of 11-12, n=64 adults) versus Low Functioning (LF = SPPB score ≤ 9, n=50 adults).

Got it. Where do ferroptosis, iron handling, and mitochondrial function come in?

Well, right here. In addition to defining High Functioning vs. Low Functioning older adults, they also collected a slew of biological measurements, including the following:

Muscle biopsy biological markers

• Mitochondrial function
• Mitochondrial damage
• Iron-handling proteins (including ferritin)

Circulating markers

• Iron regulation biomarkers
• Inflammatory cytokines
• Red blood cell indices (including hemoglobin and red blood cell distribution width, aka RDW)

A series of statistical models were then used to see if there were any differences in biological markers of ferroptosis, iron handling, and metabolic function when comparing people defined as High versus Low Functioning.

Finding #1: High- vs. low-functioning performance held across the board.

Not surprisingly, people who were categorized as High-Functioning not only had better SPPB scores, but also had better 6-minute walk distances, better handgrip strength, and better knee extensor torque compared to the Low Functioning group.

Finding #2: High-functioning folks had higher hemoglobin levels and lower RDW (red blood cell distribution width).

Of seven different clinical indices measured, only two were significantly different between the high- vs. low-functioning adults.

Specifically, high-functioning adults had:

• Higher hemoglobin. High- vs. low-functioning individuals had an average hemoglobin of 13.8 vs. 13.1 g/dL (p-value=0.010).
• Lower RDW (red blood cell distribution width). High- vs. low-functioning individuals had an average RDW of 13.7% vs. 14.2% (p-value=0.027).

Importantly, both of these are measurements of red blood cell health:

• Hemoglobin is the protein in red blood cells that carries oxygen to our tissues. Low hemoglobin is used to diagnose people with anemia.
• RDW is a measurement of the variability in red blood cell sizes. The more fragile our red blood cells, the more variability their size, and the greater the RDW.

In summary, this study showed that higher hemoglobin and lower RDW (which together translate to stronger, more stable red blood cells) were associated with high-functioning people – we’re talking people who were in their mid-70s.

Stanojevic et al. published just Part I of III of their ongoing longitudinal study, which is following this group for three years. They started with these baseline findings, but will have updates after one and three years. We look forward to their results over time.