NMN Rescues Age-Linked Susceptibility to Acute Kidney Injury
The rapid growth of an aging population creates challenges regarding diseases, and acute kidney injury is no exception. The prevalence of acute kidney disease and its associated death rate increase with age, likely due to the complex factors that contribute to the enhanced susceptibility of the renal disorder. Comorbidities like diabetes, high blood pressure (hypertension), high levels of fat in the blood (hyperlipidemia), and vascular diseases all may contribute to age-associated susceptibility to acute kidney injury. But what’s happening at the level of kidney cells during aging to cause the kidney to become more susceptible to acute injury has not been completely elucidated.
A study from Guan and colleagues found that the kidneys of old mice had reduced levels of the renal protective molecule sirtuin 1 (SIRT1) and its cofactor NAD+. Supplementation with nicotinamide mononucleotide (NMN), a precursor to the energy- and metabolism-fueling molecule NAD+, restored renal SIRT1 activity and NAD+ content in old mice and further increased both in young mice. Moreover, supplementation with NMN significantly protected mice in both age groups from toxin-induced acute kidney injury (AKI).
“Taken together, our findings reveal SIRT1 as a crucial mediator in the renal aging process,” concluded Guan and colleagues. “Furthermore, manipulation of SIRT1 activity by NMN seems to be a potential pharmaceutical intervention for AKI that could contribute to the precise treatment of aged patients with acute kidney injury.” This study sheds light on the mechanisms underlying age-associated susceptibility to AKI and identifies endogenous NAD+ as a potential therapeutic target for AKI, particularly in the elderly.
SIRT1 Certainly Confers Cell Survival
Recent studies have shown that sirtuin 1 (SIRT1) plays an important role in the cellular response to stress and has been shown to extend lifespan, at least in lower animals like worms and flies. SIRT1 has been shown to underlie calorie restriction-related health benefits, including prolonged lifespan and reduced age-related deterioration. Consistently, activators of SIRT1, including resveratrol and synthetic SIRT1-activating compounds, have been shown to promote health in experimental animals, although the results from human studies are somewhat variable, probably because of the complexities of the mechanisms of their action.
NAD+ has also been found to be an indispensable cofactor for several important enzymatic reactions, including SIRT1, supporting an important role of SIRT1 in modulating the cellular response to metabolism and oxidative stress. Accumulation studies suggest that cellular NAD+ levels reduce with aging and are accompanied by reduced SIRT1 activity. Boosting NAD+ is associated with lifespan extension, and restoring NAD+ with NAD+ precursors like NMN corrects many metabolic abnormalities.
NMN Keeps Kidneys Clear of Acute Injury
As a highly metabolically active organ that clearly is impacted by age, the kidney has emerged as an intriguing organ in which to study the consequences of NAD+ biology. That’s why Guan and colleagues examined the role of SIRT1 and NAD+ in aging and the susceptibility to acute kidney injury in animals. To do so, they compared the levels of SIRT1 and NAD+ in the kidneys of young (3-month-old) and old (20-month-old) mice. The old mice had reduced levels of the renal protective molecule sirtuin 1 (SIRT1) and its cofactor NAD+. Also, the old mice were more susceptible to acute kidney injury induced by a toxic agent. These results show that NAD+ and SIRT1 deficits in aged mice kidneys are linked to increased vulnerability to toxin-induced acute kidney injury.
But to really dig into whether NAD+ and SIRT1 have a role in age-related susceptibility to acute kidney injury, Guan and colleagues supplemented the mice with NMN. In the 20-month-old mice, NMN restored renal SIRT1 activity as well as the NAD+ content. There were also effects seen in the young 3-month-old mice, in which both SIRT1 activity and NAD+ content were increased even more. On top of that, NMN supplementation significantly protected mice in both age groups from toxin-induced acute kidney injury.
To prove that the protective effect of NMN depends on SIRT1, Guan and colleagues examined the effect of NMN on SIRT1-deficient mice and also, equivalently damaged healthy mice treated with a higher dose of the acute kidney injury-inducing toxin. What they saw was that NMN protected the kidney from severe renal injury in the non-genetically modified mice that still had SIRT1, but this therapeutic effect was substantially attenuated when one copy of the SIRT1 gene was deleted. This means that NMN rescued the toxin-induced cell death in a SIRT1-dependent manner.
This study shows that NAD+ may be an important intervention target for kidney protection. Besides, Guan and colleagues provide evidence suggesting that approaches to restore cell levels of NAD+, such as by NMN supplementation, have therapeutic potential for acute kidney injury, particularly in the elderly.
References:
Guan Y, Wang SR, Huang XZ, et al. Nicotinamide Mononucleotide, an NAD+ Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1-Dependent Manner. J Am Soc Nephrol. 2017;28(8):2337-2352. doi:10.1681/ASN.2016040385
