Key Points:
- Imai focuses on a breakthrough study revealing how NAD+ synthesis is regulated in the kidney.
- Restoring NAD+ levels could be a viable treatment for counteracting kidney aging.
According to the World Health Organization’s latest estimate, chronic kidney disease (CKD) is the ninth leading cause of death worldwide. However, despite decades of research, scientists have an incomplete understanding of the biological processes that initiate CKD. As such, there are no effective therapies that slow its progression, leading to fatal end-stage kidney disease.
In light of a recent study published in the prestigious journal Science, a pioneering researcher in the field of NAD+ metabolism, Dr. Shin-Ichiro Imai, has written an editorial describing his view on the role of NAD+ in preventing CKD. With controversy surrounding whether NAD+ is beneficial or detrimental to the kidney, we delve into the evidence.
Imai Explains the Role of NAD+ In Kidney Disease
Imai is Heavily Invested in NAD+ Research
Dr. Imai is the architect of NAD+ World 3.0, which posits that aging and longevity are regulated by NAD+-linked communication between the brain, muscle, fat, and intestines. While conducting research at the Massachusetts Institute of Technology, Imai and his colleagues discovered that NAD+ provides fuel for enzymes called sirtuins, which are now known to be key regulators of longevity. Upon becoming a professor at Washington University in St. Louis, Imai and his team helped identify a key NAD+-synthesis enzyme called NAMPT. It is now known that NAMPT declines with aging, contributing to age-related NAD+ decline.
Increasing NAD+ Synthesis Protects Against Kidney Aging
Age-related NAD+ decline is attributed to reduced NAD+ synthesis and increased NAD+ breakdown. Thus, reduced NAD-synthesis enzyme activation can lead to reduced NAD+ synthesis and the subsequent decline in cellular NAD+ levels. In the editorial, Imai explains the protective effect of an NAD+-synthesis enzyme called NMNAT against kidney deterioration. NMNAT converts the NAD+ precursor NMN to NAD+.
Imai explains that a surprise finding of the Science study was that NMNAT activity could be regulated by a recently discovered protein called PPDPF (pancreatic progenitor cell differentiation and proliferation factor).
“Cellular factors that could regulate the enzymatic activities of NAD+ biosynthetic enzymes have not been previously identified, and therefore, this discovery is a critical breakthrough in identifying such a regulatory mechanism for NMNATs,” said Dr. Imai.
The study showed that genetically removing PPDPF reduces NMNAT activity, diminishes NAD+ levels, and leads to kidney dysfunction. Moreover, administering NAD+ to mice lacking PPDPF was shown to ameliorate signs of kidney dysfunction. Furthermore, PPDPF was found to be elevated in healthy kidney cells compared to injured kidney cells. Together, these findings suggest PPDPF protects against kidney disease by increasing NMNAT activity and elevating NAD+ levels.
Notably, administering the NAD+ precursor NMN to mice lacking PPDPF did not ameliorate kidney dysfunction, likely because NAD+ levels could not be elevated due to the dysregulation of NMNAT. Following this logic, the NAD+ precursor NR (nicotinamide riboside), which is first converted to NMN before being converted to NAD+, should also fail to elevate NAD+ in kidney cells lacking PPDPF. Therefore, when it comes to potentially preventing CKD, intravenous injection of NAD+ may be the best option.
Counteracting Kidney Aging with NAD+ Precursors
In a recent pre-print (not yet peer-reviewed) study, it was shown that, in aged mice, NMN drives kidney inflammation, stirring controversy over whether NAD+ precursors are adverse or beneficial to kidney aging. However, numerous animal studies have shown that restoring NAD+ levels mitigates acute kidney injury and prevents long-term kidney damage.
In humans, the NAD+ precursor nicotinamide improved kidney function after cardiac bypass surgery, was associated with reducing the risk of death from COVID-19-related kidney injury, and improved kidney function in people with acute kidney injury. Moreover, in patients with moderate-to-severe CKD, NR was shown to reduce kidney inflammation and improve kidney health.
While more studies are needed, based on the current evidence, NAD+ precursors appear to counteract kidney deterioration. It also appears that nicotinamide and NR do not lead to adverse effects in humans. However, possibly related to defects in NMNAT activity, NMN may potentially lead to kidney inflammation. With that being said, multiple preclinical studies suggest that NMN is beneficial to kidney aging, so the one study showing it has detrimental effects may be an outlier.
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