Our Kidneys’ Keepers: How Supplemental NMN Restores Renal Function in Aged Mice

With age, there is a decline and dysfunction of all the body’s organs — and the kidneys are no exception. Although kidney disease can develop at any age, older adults are increasingly susceptible to damage or injury to these organs, with more than 50 percent of people over age 75 thought to be afflicted with kidney disease in some form.

One out of every seven Americans has chronic kidney disease — and many of them don’t know they have it, as kidney decline often develops with few or no noticeable symptoms. As chronic kidney disease can quickly develop into more serious stages, ending with dialysis and the need for kidney transplants, it’s vital to increase our understanding of why these bean-shaped organs age — and what we can do about it. 

In a recent study published in Aging, researchers out of Beijing, China, aimed to do just that, using a compound called nicotinamide mononucleotide (NMN). This precursor to nicotinamide adenine dinucleotide (NAD+), an essential coenzyme whose levels tend to decrease with age, concurrent with the decline of organ function. Research has shown that supplementing with NMN boosts NAD+ levels, mitigating organ dysfunction and slowing down the aging process in animals. In this study, Yi and colleagues used supplemental NMN to normalize several proteins implicated in the aging and dysfunction of the kidneys of older mice. 

Finding needles in a haystack: using proteomics to pinpoint proteins of kidney aging 

The kidneys’ primary jobs include filtering out and removing waste products, drugs, and excess fluid from the body while balancing overall fluid and salt balance. The main structure involved with waste filtration is the glomerulus — a small cluster of blood vessels that acts as a microscopic filter. With age, glomerulus function drops, reducing filtration rates and leading to kidney disease. Previous research has found thousands of proteins involved in these crucial roles of the kidney, but scientists haven’t been precisely sure which proteins are directly related to aging. 

Through the lens of proteomics, or the large-scale study of proteins, Yi and colleagues looked at thousands of potential proteins that may play a role in kidney health. While previous research has not yet been able to define consistent proteomic results for biomarkers of kidney aging, this research team narrowed down the thousands of proteins to just 27. By looking at proteins whose levels are different between the kidneys of young, 8-week old mice and old, 96-week old mice (translating to about 70 human years), Li and colleagues are one step closer to pinpointing how and why our kidneys age.

Detailing the dysregulated proteins of aging kidneys

Nineteen out of the 27 identified proteins were increased, or upregulated, in the aged mice, while the other eight were decreased, or downregulated. One protein that was highly upregulated in the older kidneys was aldehyde dehydrogenase-1 (ALDH1A1). While this enzyme is essential for the metabolism of alcohol, drugs, and retinol (vitamin A), its overexpression is implicated in several diseases, including kidney disease.

Some of the downregulated proteins were peroxisomes — small structures inside cells that contain over 50 vital enzymes needed to complete various metabolic reactions. Although they are present in cells throughout the body, peroxisomes are most abundant in the kidneys and liver. These organelles, or organs of cells, are beneficial because they degrade the inflammatory reactive oxygen species (ROS) that accumulate in and damage cells by causing oxidative stress. As with other organs and systems in the body, oxidative stress is a significant contributor to kidney damage and aging. Two other enzymes that aged mouse kidneys had diminished levels of were catalase and glutaredoxin-1, both of which inhibit ROS and reduce oxidative damage. 

Bringing proteins back into balance with NMN

After identifying the protein-related differences between old and young mouse kidneys, Yi and colleagues treated the aged mice with supplemental NMN every other day for four weeks, at doses of 500 milligrams (mg) per kilogram of body weight. For a human dose, this would equate to approximately 2,000 mg (2 grams) of NMN every other day.

After the four weeks, the NMN-treated mice experienced significant reversals in almost all of the dysregulated proteins. Sixteen out of the 19 proteins that were overexpressed with age had their levels reduced back to normal, while six out of the eight underexpressed proteins were increased back to youthful levels. With these reversals, NMN successfully rescued the aging mouse kidneys from proteostasis loss — when proteins are unable to maintain proper homeostasis, or balance. When this loss occurs, protein activity can become either too high or too low to be functional, or proteins become misfolded and can’t do their jobs As one of the hallmarks of aging, this loss of protein homeostasis, or balance, is intrinsically linked to increased aging of the kidneys — and all organs — as imbalanced or misfolded proteins can’t do their job correctly.

One of the proteins that NMN reduced was ALDH1A1, which the researchers believe could be a potential therapeutic target for treating kidney aging. Conversely, NMN increased levels of Pck1, the protein that was most significantly downregulated in the aged kidneys. Pck1 is involved in gluconeogenesis — the process of the liver and kidneys creating their own glucose to supply the brain and muscles with energy. Low levels of Pck1 are implicated in aging and shorter lifespans of mice. 

Lastly, NMN significantly mitigated the age-related loss of peroxisome quantity and activity, suggesting that NMN could reduce the damaging ROS buildup in the kidneys. Also related to oxidative stress, NMN reversed the low levels of the antioxidant enzymes catalase and glutaredoxin-1 that were seen in the aged mouse kidneys. 

Aging kidneys and humans: what’s next?

While these results are promising for older mice with kidney disease, we don’t know yet if these 27 proteins are also dysregulated in aging humans’ kidneys. If the proteomic analyses were found to be similar between mice and humans, it could open doors for using mouse proteomes to assess other aspects of human aging. As we already know that low levels of antioxidant enzymes and peroxisomes are implicated in a myriad of diseases, the next step would be to see if supplemental NMN can mitigate these losses to protect against kidney disease in humans. 

References: 

Hakimi P, Yang J, Casadesus G, et al. Overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse. J Biol Chem. 2007;282(45):32844-32855. doi:10.1074/jbc.M706127200

Vasko R. Peroxisomes and Kidney Injury. Antioxid Redox Signal. 2016;25(4):217-231. doi:10.1089/ars.2016.6666

Yi M, Ma Y, Zhu S, et al. Comparative proteomic analysis identifies biomarkers for renal aging. Aging (Albany NY). 2020;12(21):21890-21903. doi:10.18632/aging.104007