Hollywood Loves NAD - But Science Isn’t So Sure

NAD+ (Nicotinamide adenine dinucleotide) is one of the most talked-about molecules in the longevity world. It plays a critical role in energy metabolism, DNA repair, and mitochondrial function. As we age, NAD+ levels decline, and that decline has been linked to fatigue, muscle loss, and slower recovery.

This led to the rise of NAD+ boosters like NMN and NR, marketed as anti-aging interventions aiming to restore what time takes away.

But what if we’ve misunderstood the relationship?

New Research: Muscles Function Normally Despite NAD+ Loss

A groundbreaking Cell Metabolism study (2024) put the NAD+ theory to the test. Researchers genetically deactivated Nampt, a critical enzyme in the NAD+ salvage pathway, in adult mice, causing an 85% reduction in NAD+ levelsspecifically in skeletal muscle.

The results were surprising:

• Muscle strength and endurance remained normal

• Mitochondria continued functioning effectively

• No acceleration in biological aging (measured via DNA methylation clocks)

• Metabolic health markers like glucose tolerance were unchanged

Despite such a severe depletion of NAD+, the muscle tissue was remarkably resilient.

This challenges the idea that NAD+ decline is a primary driver of muscle aging. Instead, it may be a byproduct, a downstream effect of deeper dysfunctions like inflammation, mitochondrial impairment, or cellular stress response failure.

Downstream vs. Upstream: Where Should We Intervene?

Think of NAD+ as fuel. Supplying more of it via NMN or NR is like topping off the gas tank, but what if the real problem is a failing engine?

NAD+ supplementation is a downstream intervention: it temporarily raises levels of a molecule whose decline might reflect upstream breakdowns, like inflammation, mitochondrial dysfunction, or impaired stress responses. It doesn’t restore the body’s innate ability to maintain NAD+, nor does it repair the underlying systems that rely on it.

This is why a growing number of researchers now advocate targeting upstream mechanisms, particularly mitochondrial health and inflammation, as more effective levers for promoting longevity.

Enter Urolithin A: A Mitochondrial Makeover

One of the most promising upstream interventions is Urolithin A — a postbiotic compound produced by gut microbes from dietary ellagitannins (found in foods like pomegranate and walnuts). Urolithin A doesn’t raise NAD+ directly. Instead, it restores mitochondrial health by stimulating two essential processes:

• Mitophagy — the clearance of dysfunctional mitochondria

• Mitogenesis — the creation of new, efficient mitochondria

As we age, mitochondrial turnover slows, leading to accumulated damage, reduced energy output, and increased oxidative stress, ...