When Energy Traffic Slows: NAD⁺, Mitochondria, and the Rhythm of the Aging Heart

A recent study published in Communications Biology explored a fascinating question: Why does the heart’s circadian rhythm weaken as we age—and can restoring NAD⁺ help?

The research suggests that declining NAD⁺ levels may disrupt the heart’s internal clock and contribute to cardiac aging. But these findings also point to a deeper question: Why does NAD⁺ decline in the first place?

Viewed through the lens of Exposure-Related Malnutrition (ERM) and mitochondrial bioenergetics, this study offers an intriguing glimpse into how energy congestion inside mitochondria may ripple outward to affect cellular timing and systemic physiology.

The Heart Has a Clock

Every cell in the body follows a circadian rhythm, coordinated by molecular clock genes such as:

• CLOCK

• BMAL1

• PER

• CRY

These genes orchestrate daily cycles of metabolism, repair, and energy use.

In the heart, circadian regulation helps synchronize:

• fuel selection

• mitochondrial metabolism

• contractile function

• stress responses

Disruptions to this rhythm have been linked to metabolic disease, cardiovascular dysfunction, and aging.

The new study by Carpenter and colleagues asked a simple but important question:

How does aging affect the circadian program of the heart—and what role does NAD⁺ play?

What the Study Found

The researchers compared young and old mouse hearts and discovered a striking shift in circadian biology.

Aging reduces rhythmic gene expression

In young hearts, over 1,200 genes oscillated with daily rhythms.

In older hearts, this dropped dramatically to around 300 genes.

This suggests that aging does not merely slow metabolism—it disrupts the rhythmic coordination of metabolic pathways.

NAD⁺ levels fall with age

The study also confirmed that cardiac NAD⁺ levels decline with aging.

NAD⁺ is one of the most important molecules in cellular metabolism. It acts as:

• a redox carrier in mitochondrial respiration

• a substrate for enzymes such as sirtuins

• a regulator of circadian clock proteins

When NAD⁺ declines, these systems begin to lose coordination.

NAD⁺ supplementation restores rhythmicity

When the researchers supplemented aging mice with nicotinamide riboside (NR)—a precursor of NAD⁺—several changes occurred:

• circadian gene expression partially recovered

• cardiac hypertrophy was reduced

• stress-response genes declined.

In cultured heart cells, reducing NAD⁺ levels directly disrupted circadian oscillations, while restoring NAD⁺ brought the rhythms back.

The Acetylation Connection

One important mechanism appears to involve protein acetylation.

The study observed that aging hearts develop increased global protein acetylation, likely due to reduced activity of NAD⁺-dependent deacetylases such as SIRT1.

SIRT1 normally regulates circadian proteins including:

• PER2

• BMAL1

• CLOCK

When NAD⁺ levels fall, SIRT1 activity declines, creating a more hyperacetylated cellular environment.

This biochemical shift alters the regulation of circadian genes and weakens their rhythmic oscillations.

An ERM Perspective: When Mitochondria Become Congested

The study demonstrates that NAD⁺ influences circadian rhythms, but it does not fully address why NAD⁺ declines during aging.

The ERM framework offers a possible upstream explanation.

ERM proposes that chronic exposures—metabolic stress, toxins, inflammation, or nutrient imbalance—can create bioenergetic congestion inside mitochondria.

Think of the mitochondria as a highway system for electrons.

When everything flows smoothly, electrons move through the electron transport chain (ETC) to generate ATP.

But when metabolic inputs exceed mitochondrial capacity, traffic begins to build up.

Reducing equivalents begin to accumulate

During congestion, molecules such as:

• NADH

• FADH₂

accumulate faster than the ETC can process them.

This creates reductive pressure, shifting the redox balance toward NADH.

NAD⁺ availability falls

Because NAD⁺ and NADH form a redox pair, excess NADH effectively limits the pool of available NAD⁺.

Lower NAD⁺ availability reduces the activity of enzymes that depend on it—including SIRT1.

A hyperacetylated state emerges

Reduced SIRT1 activity allows acetylation marks on proteins to accumulate.

This produces a hyperacetylated cellular environment, which alters transcriptional regulation across multiple pathways—including circadian gene networks.

Circadian rhythms weaken

Over time, the sequence may look like this:

Mitochondrial congestion

↓

Accumulation of reducing equivalents

↓

Lower NAD⁺ availability

↓

Reduced SIRT1 activity

↓

Hyperacetylation of cellular proteins

↓

Disruption of circadian gene regulation

↓

Loss of rhythmic metabolic coordination

From this perspective, circadian disruption may be an early signal of underlying bioenergetic strain.

Why Circadian Rhythms Matter for Aging

Circadian rhythms are not merely about sleep cycles.

They regulate critical processes including:

• mitochondrial respiration

• DNA repair

• immune activity

• hormone secretion

• metabolic flexibility

When rhythmic coordination weakens, the body becomes less efficient at allocating energy across these systems.

The result may be a gradual shift toward:

• chronic inflammation

• metabolic disease

• impaired recovery

• accelerated aging

Restoring Rhythm

The new study shows that increasing NAD⁺ levels can partially restore circadian rhythmicity in aging hearts.

But the broader lesson may be even more important:

Circadian disruption may be a downstream consequence of mitochondrial stress.

If so, strategies that improve mitochondrial throughput—such as restoring metabolic flexibility, reducing chronic exposures, and improving nutrient utilization—may help preserve both bioenergetic health and circadian integrity.

A New Way to Think About Aging

The findings from this study suggest that aging may involve more than simple wear and tear.

Instead, it may reflect a gradual loss of coordination in the body’s energy systems.

Mitochondria sit at the center of this network.

When their capacity becomes constrained, the effects may extend far beyond ATP production—reaching into redox balance, epigenetic regulation, and even the timing mechanisms that govern cellular life.

Understanding this deeper bioenergetic layer may open new paths for addressing aging and chronic disease—not by forcing the body harder, but by helping its energy systems flow more freely again.

Reference

Carpenter, B.J., Lecacheur, M., Mangold, Y.N. et al. NAD⁺ controls circadian rhythmicity during cardiac aging. Commun Biol  (2026). https://doi.org/10.1038/s42003-026-09818-1