What is NAD World 3.0?

The NAD World 3.0 is the newest version of a framework that explains how aging and longevity in mammals are regulated through NAD+ (nicotinamide adenine dinucleotide) metabolism.

Shin-Ichiro Imai and his team came up with this theory in 2025¹, building on their earlier ideas from 2009 and 2016 while adding important new elements. These include the small intestine as a key tissue, the Slc12a8 NMN transporter, and extracellular NAMPT (eNAMPT)-containing vesicles.

The core idea is that aging happens when multi-layered feedback loops break down – these loops involve NMN (nicotinamide mononucleotide) and eNAMPT working across four main tissues: the hypothalamus, skeletal muscle, adipose tissue, and small intestine.

This paradigm shift gives us much better insights into how declining NAD+ throughout the body drives aging and points to new targets for potential treatments.

From NAD World 1.0 to 2.0: Laying the Foundation

The NAD World hypothesis (2009) put NAD+ at the center of mammalian aging by showing how it works through sirtuin-mediated deacetylation and circadian rhythm regulation².

This idea highlighted two key players:

• SIRT1, an NAD+-dependent deacetylase that controls DNA repair, metabolism, and stress resistance
• NAMPT, the rate-limiting enzyme in the NAD+ salvage pathway that’s responsible for making NAD+ throughout the body.

By 2016, new findings led to an update called NAD World 2.0³, which added three important tissues to the picture:

• The hypothalamus as the control center for aging
• Skeletal muscle as the mediator of metabolism
• Adipose tissue as the modulator of NAD+.

This newer version highlighted how tissues talk to each other through adipose-derived eNAMPT vesicles and how the hypothalamus sends sympathetic signals to peripheral tissues.

But we still didn’t know enough about how NMN moves through the body and how different tissues maintain their NAD+ levels—gaps that the 3.0 version tries to fill.

Advancements Leading to NAD World 3.0

Three breakthroughs pushed us into NAD World 3.0:

• Finding Slc12a8 as the main NMN transporter that lets cells directly take up NMN.
• Understanding how eNAMPT-containing extracellular vesicles (EVs) work as long-range carriers for NAD+ biosynthesis.
• Discovering the small intestine’s role as the fourth pillar in controlling systemic NAD+ through NMN absorption and circulation.

These discoveries showed us previously hidden layers of time and space control over NAD+ balance. We now need a model that includes both quick (minutes) NMN transport and slower (hours/days) eNAMPT-driven NAD+ synthesis.

The Four Pillars of NAD World 3.0

Think of NAD World 3.0 as a communication network between four major “control centers” in your body:

1. The Hypothalamus: The Brain’s Command Center

Deep in the brain, the hypothalamus works like a control center, maintaining the vital systems that guide your body’s cells throughout life. It:

• Sends signals to muscles and fat tissue
• Controls essential conditions like temperature and hunger
• Uses NAD+ as a key resource to keep biological processes running properly

When the hypothalamus doesn’t have enough NAD+, its function declines, causing your body’s cells to operate less efficiently and potentially speed up the aging process.

2. Skeletal Muscle: The Power Generator

Your muscles are your body’s biggest users of NAD+. They:

• Burn energy to move your body
• Release special molecules called myokines that affect other tissues
• Work closely with the hypothalamus through a feedback system

As you age and NAD+ levels drop, muscle weakness and fatigue can result.

3. Fat Tissue: The Communication Hub

Your fat cells do more than just store energy. In NAD World 3.0, they:

• Package NAMPT (the enzyme that makes NAD+) into tiny bubbles called vesicles
• Send these vesicles through your bloodstream to other tissues
• Help maintain NAD+ levels throughout your body

This explains why changes in body fat can affect how we age.

4. Small Intestine: The Supply Manager

The newest addition to the theory, your small intestine:

• Absorbs NMN (the direct precursor of NAD+) from your diet
• Contains high levels of the Slc12a8 transporter to capture NMN
• May interact with gut bacteria that produce NAD+ precursors

This explains why diet may significantly impact how we age.

How the System Works Together

NAD World 3.0 describes two main ways these systems work together:

The Fast Lane: Quick NAD+ Adjustments

When your body needs quick energy or repair:

1. The small intestine absorbs NMN from food
2. The Slc12a8 transporter quickly moves NMN into cells
3. Cells convert NMN to NAD+ within minutes
4. This NAD+ powers immediate cellular needs

This is like having a fast-charging system for your cellular batteries.

The Slow Lane: Long-Term NAD+ Maintenance

For ongoing NAD+ support:

1. The hypothalamus signals fat tissue
2. Fat tissue releases NAMPT-containing vesicles
3. These vesicles travel to tissues that need NAD+
4. The tissues use NAMPT to make NAD+ over hours or days

This system keeps your NAD+ levels stable over time, like a backup generator.

What This Means for Anti-Aging Treatments

NAD World 3.0 suggests several promising approaches to slow aging:

1. NMN Supplements: Taking pure NMN could boost NAD+ levels, especially if absorbed by the small intestine.
2. NMNH: A modified form of NMN that might better reach the brain.
3. Slc12a8 Enhancers: Drugs that increase this transporter could improve NMN absorption.
4. Targeted Delivery Systems: Special particles that deliver NAD+ precursors to specific tissues.
5. Gut Microbiome Approaches: Probiotics with bacteria (Fructobacillus) that produce NAD+ building blocks.

The Big Picture

The NAD World 3.0 theory is a big step forward in how we understand aging. Instead of just looking at single cells or genes like older theories did, this framework shows how different body systems work together during the aging process.

This theory suggests aging isn’t simply about wearing out over time. It’s actually caused by the breakdown of a complex communication network between your brain, muscles, fat tissue, and intestines—all linked by NAD+.

As scientists test and refine this theory, we might find new ways to keep our NAD+ levels up as we get older. This could potentially slow down age-related decline and help us stay healthy longer.

The science is still evolving, but NAD World 3.0 gives us a fresh roadmap for understanding one of life’s biggest mysteries: why and how we age.

Referenced Sources

1. https://www.nature.com/articles/s41514-025-00192-6 ↩︎
2. https://pmc.ncbi.nlm.nih.gov/articles/PMC2734380/ ↩︎
3. https://www.nature.com/articles/npjsba201618 ↩︎