When We Think About the Liver and Kidneys, We Often Say: “The Liver Detoxifies, the Kidneys Excrete Waste.”
But in the popular discussion about how to scientifically extend lifespan, these two organs are often painted as the classic symbols of decline with age. We tend to focus on how to protect them from age-related damage, rather than expecting them to play an active role in anti-aging.
However, a recent groundbreaking study published in Cell Metabolism [1] reveals something surprising:
Far from being aging “burdens,” our liver and kidneys can actually work together to help maintain NAD⁺ balance in the body through a molecule called nicotinic acid riboside (NaR). This “liver-kidney axis” protects organs throughout the body and helps fight aging!
🏃♂️ The NAD⁺ Relay Between the Liver and Kidneys
You probably already know the importance of NAD⁺:
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It’s a participant in nearly half of all basic biochemical reactions inside cells.
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It serves as an electron carrier during ATP production.
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It’s essential for DNA repair and maintaining genomic stability.
In short, if your body has enough NAD⁺, your aging process may slow down.
Now let’s talk about NAD⁺ metabolism. The liver acts as the central hub of NAD⁺ metabolism:
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It breaks down NAD⁺ into nicotinamide (NAM).
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NAM circulates in the blood and is taken up by other organs to synthesize their own NAD⁺.
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This creates a “recycle-and-reuse” system for NAD⁺ throughout the body.
📊 Diagram: Pathways for NAD⁺ and nicotinamide production in the liver (1. de novo synthesis from tryptophan; 2. Preiss-Handler pathway from niacin; 3. salvage pathway using NAM or NR)
🧬 The Bottleneck: NMNAT1
Looking at all these pathways, one crucial enzyme stands out: NMNAT1 (nicotinamide mononucleotide adenylyltransferase 1). No matter where NAD⁺ synthesis begins, it ultimately depends on NMNAT1.
So what happens if NMNAT1 malfunctions?
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NAD⁺ levels plummet.
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Its precursors (NaMN and NMN) accumulate in excess.
📊 Figure: In NMNAT1 liver knockout (LKO) mice, NAD⁺ synthesis in the liver is disrupted
As expected, deleting NMNAT1 impairs NAD⁺ production in the liver. But surprisingly, when scientists tracked labeled tryptophan (a precursor in NAD⁺ synthesis) in LKO mice, the rest of the body’s NAD⁺ levels remained stable, despite the liver’s NAD⁺ synthesis being essentially “shut down.”
📊 Figure: NAD⁺ and nicotinamide levels in other tissues remain unchanged
This was puzzling. How could systemic NAD⁺ remain steady when the liver’s NAD⁺ machinery had failed?
🧪 The Discovery of NaR: A Backup Pathway
Metabolomic and mass spectrometry analyses revealed a molecule whose levels surged 30-fold in LKO mice: nicotinic acid riboside (NaR).
Here’s what scientists hypothesized:
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Excess NaMN in the liver might be converted to NaR by removing a phosphate group.
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This type of reaction is usually catalyzed by the NT5C enzyme family.
📊 Figure: Similar to the dephosphorylation of CMP to cytidine, NaMN could be converted to NaR
When researchers interfered with NT5C2 expression, NaR production in liver cells dropped significantly. Both genetic knockout and inhibitor treatment blocked NaR synthesis and release.
📊 Figure: NT5C2 disruption suppresses NaR production and export in liver cells
So when the liver’s NMNAT1 function is compromised and NaMN builds up, the liver activates an emergency pathway:
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NT5C2 converts NaMN into NaR,
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NaR is released into the bloodstream.
🩺 The Kidneys Take Over
Where does circulating NaR go? Straight to the kidneys.
The kidneys were the only organ found to rapidly and abundantly convert labeled NaR into NaAD (a direct NAD⁺ precursor) and then into NAD⁺.
In LKO mice, circulating NaR accounted for:
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~100% of kidney NaAD
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~75% of kidney NAD⁺
📊 Figure: The kidneys efficiently use NaR from circulation to produce NAD⁺, even when liver NAD⁺ synthesis is impaired
This process requires a team of enzymes:
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NRK1 phosphorylates NaR into NaMN.
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NMNAT1 converts NaMN to NaAD.
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NADSYN converts NaAD to NAD⁺.
Among these, NRK1 is critical. Without it, kidney cells cannot efficiently process NaR into NAD⁺.
📊 Figure: Reduced NRK1 expression blocks kidney conversion of NaR to NAD⁺
After producing NAD⁺, the kidneys also degrade it into nicotinamide (NAM), releasing NAM into the bloodstream for other tissues to recycle into NAD⁺.
📊 Figure: The kidneys are net consumers of NaR (V/A ratio <0) and net producers of NAM (V/A ratio >0)
🔥 Aging and the NaR Pathway
As we age, NAD⁺ levels naturally decline. Does this newly discovered liver-kidney NaR axis play a role?
The answer: yes. And it’s affected by aging.
1️⃣ Decline in Circulating NaR
Blood samples from young (3-month-old) and aged (25-month-old) mice showed that aged mice had significantly lower NaR levels.
2️⃣ Reduced Liver Production
The aging liver’s ability to convert tryptophan into NaR drops sharply due to reduced enzyme expression.
📊 Figure: Expression of multiple NaR-synthesizing enzymes declines with age
3️⃣ Kidney Inefficiency
The aging kidney struggles too. Aged mice had:
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Lower total NAD⁺ and NAM levels.
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Reduced ability to convert labeled precursors into NAD⁺.
This suggests that even if precursors are available, aging kidneys can’t efficiently maintain NAD⁺ homeostasis.
💊 Can Supplementation Help?
✅ Direct NaR Supplementation
When scientists added NaR to the drinking water of aged mice for 2 weeks, they found:
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Increased circulating NaR and downstream metabolites (NaAD, NAM).
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Restored NAD⁺ balance in multiple tissues, especially the kidneys.
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Reduced kidney damage and inflammation markers (e.g., Kim1, Fgl2).
Most importantly, NaR supplementation improved kidney function, lowering urine albumin-to-creatinine ratio (ACR) — a key indicator of renal health.
📊 Figure: NaR restores kidney function and reduces proteinuria in aged mice
✅ A Plan B: Niacin (Vitamin B3)
NaR supplements are not yet widely available. But there’s an alternative: niacin (vitamin B3), the starting molecule in the Preiss-Handler pathway.
When niacin was administered to wild-type mice:
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Liver levels of NaMN and NaR rose.
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Kidney levels of NaMN, NaAD, and NAD⁺ also increased.
This suggests niacin can support the liver-kidney NaR axis.
And the best part? Niacin is abundant in foods like peanuts, tuna, and organ meats [2].
📊 Figure: Foods rich in niacin (highlighted in red)
By maintaining a balanced diet with niacin-rich foods, you may not only meet your body’s vitamin B3 needs but also support your liver-kidney NaR axis, maintain NAD⁺ levels, and protect against age-related decline.
✅ This exciting new research suggests that supporting the liver-kidney NaR axis could be a promising strategy for anti-aging.