NAD⁺, Anti-Aging Hype, and the Mitochondrial Traffic Jam

Why NAD⁺ “works” in some studies—and fails in many real people

Every few years, a molecule becomes the new darling of longevity science.

For the past decade, that molecule has been NAD⁺.

Boost your NAD⁺, we’re told, and you can:

• Rejuvenate mitochondria

• Restore energy

• Slow aging

• Improve brain and muscle function

A new study published in JCI Insight adds more fuel to this narrative, showing that NAD⁺ precursors can dramatically improve mitochondrial function and behavior in a genetic mitochondrial disease model.

But here’s the crucial point most headlines miss:

This study does not model the kind of mitochondrial dysfunction most people have.

And that difference explains why NAD⁺ sometimes works beautifully—and often doesn’t.

What the study actually showed

The researchers studied a rare mitochondrial disease caused by a defect in a single enzyme of the TCA cycle: succinyl-CoA ligase (SUCLA2).

In this model:

• One metabolic step is blocked

• A specific metabolite (succinyl-CoA) accumulates

• This causes excessive chemical modification of mitochondrial proteins (“succinylation”)

• Cleaning up that damage consumes NAD⁺

• Over time, NAD⁺ becomes depleted

• Mitochondrial energy production fails

When the researchers supplied NAD⁺ precursors (nicotinamide and nicotinamide riboside):

• NAD⁺ levels were restored

• Damaged proteins could be repaired

• Mitochondrial respiration improved

• Movement, feeding behavior, and survival improved

This is solid, elegant biology.

But it’s also a very specific metabolic scenario.

Why NAD⁺ worked here

In this disease model, the mitochondria are not overloaded.

They are:

• Partially functional

• Limited by cofactor availability (NAD⁺)

• Struggling to clean up localized metabolic damage

In this context, NAD⁺ is the rate-limiting factor.

Adding NAD⁺ helps because:

• The metabolic “roads” are still open

• The system just lacks enough “repair currency”

• Restoring NAD⁺ re-enables normal housekeeping

Think of it like a city with a garbage workers’ strike:

• Streets are empty

• Infrastructure is intact

• The problem is a missing workforce

• Hire workers → city recovers

Why this is not the same as most aging, fatigue, or metabolic disease

Most people interested in NAD⁺ supplements are not suffering from a rare enzyme deficiency.

They’re dealing with something very different:

Mitochondrial congestion

In congestion:

• Substrates are abundant (glucose, fats, amino acids)

• The TCA cycle is already saturated

• NADH is high, NAD⁺ regeneration is constrained

• The electron transport chain is backed up

• Citrate spills out into the cytosol

• Cells shift toward storage and inflammation

• Repair is deferred because throughput—not cofactors—is the limit

This is not a NAD⁺ shortage problem.

It’s a traffic jam problem.

Adding more NAD⁺ here is like:

• Giving more gas money to cars stuck on a highway with no exits

• You may rev the engine, but you don’t go anywhere

At best, NAD⁺ supplementation may:

• Improve signaling markers

• Slightly shift redox tone

• Provide temporary symptom relief

But it cannot restore flow if the system is gridlocked.

Why the NAD⁺ hype persists

Both models exist, but they get conflated.

NAD⁺ supplementation works when:

• Mitochondria are underutilized

• Damage repair is limited by NAD⁺ availability

• Congestion has not yet developed

• The system still has spare processing capacity

NAD⁺ supplementation disappoints when:

• Mitochondria are chronically overloaded

• Energy intake exceeds processing capacity

• Stress signaling is sustained

• Repair windows never open

Most human chronic disease lives in the second category.

The real lesson from this study

This paper doesn’t prove that NAD⁺ is a universal anti-aging solution.

It proves something more important:

Context determines whether NAD⁺ is therapeutic or cosmetic.

The study actually strengthens a more nuanced framework:

• Early, localized mitochondrial dysfunction may be NAD⁺-responsive

• Advanced, systemic mitochondrial congestion is not

• Supplements cannot substitute for restoring metabolic flow

Bottom line

You’re not “NAD⁺ deficient” because you’re aging.

You’re exhausted because your mitochondria are congested.

Until congestion is relieved—by reducing load, restoring rhythm, and reopening recovery windows—adding more NAD⁺ is unlikely to deliver the promised rejuvenation.

You’re not broken.

You’re backed up.

And traffic jams aren’t fixed by adding fuel.

Richard, J., Lizzo, G., Rochat, N., Jouary, A., Silva, P. T. M., Parisi, A., Christen, S., Moco, S., Orger, M. B., & Gut, P. (2026). NAD⁺ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations. JCI Insight, 11(2), e181812. https://doi.org/10.1172/jci.insight.181812