Another Review Confirms the Problem — But Integration Is Still Missing

Why mitochondrial dysfunction links aging, insulin resistance, and inflammation — and why medicine still treats them separately.

A recent review published in Metabolites (2025) by Hao et al., “Relationship of Ageing to Insulin Resistance and Atherosclerosis”, delivers a clear and important message:

Aging, insulin resistance, chronic inflammation, and atherosclerosis are not separate diseases — they are biologically connected through mitochondrial dysfunction.

This is not a radical claim. But the way the review assembles the evidence makes something undeniable: mitochondrial failure sits upstream, while insulin resistance (IR), chronic systemic inflammation (CSI), and vascular dysfunction appear downstream as linked consequences.

And yet — despite this convergence — our medical and research systems still treat these conditions as if they were unrelated.

What the Metabolites review clearly establishes

The review by Hao and colleagues synthesizes evidence showing that:

• Aging is accompanied by declining mitochondrial efficiency and impaired mitophagy

• Mitochondrial dysfunction increases reactive oxygen species (ROS) and redox imbalance

• These changes impair insulin signaling, promote hyperinsulinemia, and drive endothelial dysfunction

• Chronic low-grade inflammation (“inflammaging”) emerges through persistent immune activation

• Insulin resistance and atherosclerosis amplify one another in a self-reinforcing cycle

Crucially, the review frames mitochondrial dysfunction as an upstream driver, not merely a downstream casualty.

This alone challenges glucose-centric and cholesterol-centric thinking.

But it also raises an uncomfortable question:

If we already know these processes are connected, why do we still treat them as separate problems?

Where the Exposure-Related Malnutrition (ERM) framework adds what’s missing

This is where the ERM framework becomes relevant.

ERM does not contradict the review — it extends it by offering a continuous, energetically grounded explanation of how these conditions emerge over time.

ERM reframes the story as a metabolic continuum:

1. Chronic exposures

   Nutritional mismatch, psychosocial stress, inflammation, toxins, and sleep disruption

2. Metabolic stress adaptation

   The body reallocates energy toward survival

3. Mitochondrial constraint

   ATP production, redox balance, and recovery capacity become limited

4. Downstream expressions

   • ROS accumulation

   • Insulin resistance as an adaptive brake

   • Chronic sterile inflammation

   • Progressive tissue and vascular dysfunction

In this model, insulin resistance and inflammation are not primary diseases — they are signals that energetic resolution has failed.

The Metabolites review describes the mechanisms.ERM provides the directionality and continuity.

Why fragmentation persists — despite reviews like this one

Even with reviews as integrative as Hao et al., three structural problems remain.

1. Medicine is organized around endpoints, not trajectories

• Diabetes focuses on glucose

• Cardiology focuses on plaques

• Immunology focuses on inflammation

• Aging research focuses on senescence

Each field studies a snapshot, not the adaptive journey.

ERM focuses on the path from exposure to failure, not the endpoint alone.

2. Stress adaptation is discussed without energetic accounting

Concepts like resilience, hormesis, and allostasis are widely used — but rarely measured in energetic terms.

ERM makes a simple but disruptive claim:

Adaptation has a metabolic cost. If recovery is incomplete, energetic debt accumulates.

The review implies this.ERM makes it explicit.

3. Mitochondria are acknowledged — but not treated as system governors

In most models, mitochondria are:

• Damaged by inflammation

• Worn down by aging

• Secondary to disease

ERM places mitochondria where the review’s evidence already points:

as the limiting infrastructure for resolution, repair, and resilience.

Without restoring mitochondrial capacity, suppressing downstream signals cannot fully restore health.

Why this matters clinically

When conditions are treated in isolation:

• Glucose improves, but fatigue remains

• Inflammation markers fall, but recovery doesn’t return

• Lipids normalize, but resilience continues to decline

ERM reframes the clinical question:

Where is this person along the exposure → adaptation → constraint → failure continuum?

That question changes:

• What we measure

• When we intervene

• What “improvement” truly means

A hopeful conclusion

The review by Hao et al. (Metabolites, 2025) strengthens an essential point:aging-related metabolic disease follows a coherent biological logic.

ERM adds what is still missing:

• A continuous trajectory

• An energetic accounting of adaptation

• A unifying explanation for why IR, CSI, and dysfunction cluster together

• And a framework for earlier, more meaningful intervention

The obstacle is no longer a lack of data.

It is a lack of integration.

And integration is exactly where the next phase of metabolic and aging medicine must go.

Hao, X., et al. (2025). Relationship of ageing to insulin resistance and atherosclerosis. Metabolites, 15(6), 613. https://doi.org/10.3390/metabo15060613