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March 22, 2021

NMN ameliorates age-associated physiological decline

NMN ameliorates age-associated physiological decline

Our bodies have been creating NMN for millennia, yet only now are we arebeginning to understand the role this vital molecule plays in health andlongevity. At Seneque, our extensive program of clinical trials is analyzingfor the first time in humans the effects of NMN on several pathophysiologiesassociated with the aging process.

Our research isadvancing the path forged by groundbreaking preclinical research thatestablished proof-of-concept of NMN’s therapeutic potential. Foundational to ourongoing progress has been research undertaken by scientists at WashingtonUniversity School of Medicine (WUSM), which showed that long-termadministration of NMN is remarkably capable of ameliorating age-associatedphysiological decline in mice [1].

 

Pioneering NMN research

The 2016 study was pioneeringin the NAD+ field as it was the first and only study to evaluate thephysiological and toxicity effects of a long-term (1 year) administration ofNMN in mice during normal aging. Research under the same parameters has not beenconducted for other NAD+ precursors. For example, in the WUSM study, NMN wasgiven at lower doses which could be translatable to humans, rather than chronicadministration as per studies on other NAD+ precursors. Furthermore, beneficialeffects were seen in regular diet mice, as opposed to the high fat diet miceused in other studies.

 

Short- and long-term benefits

Researchers, including Seneque ChiefScientist Dr. Alessia Grozio, evaluated the impact of NMN over an extendedtimeframe after highly promising results from previous studies showed thatshort-term administration of NMN:

·      ameliorates impairments in glucose-stimulatedinsulin secretion [2],

·      significantly improves bothinsulin action and secretion in diet- and age-induced type 2 diabetic or obesemouse models [3],

·      protects the heart fromischemia/reperfusion injury by preventing NAD+ decrease induced by ischemia [4],

·      maintains the neural stem/progenitorcell population [5],

·      restores skeletal musclemitochondrial function and arterial function in aged mice [6] [7], and

·      ameliorates mitochondrialfunction, neural death, and cognitive function in Alzheimer’s disease rodentmodels [8] [9].

Results from the WUSM study showed that notonly is NMN well-tolerated over 12 months and quickly used to synthesize NAD+in tissues, but also that oral intake of NMN delivers preventive effects which improvehealthspan.

 

NMN suppresses age-associated weightgain

In the study, researchers observed that a subjectgroup receiving 300 mg/kg/day of NMN tended to have a decreased fat mass andincreased lean mass compared to control subjects. After 12 months of NMNadministration, the average percent body weight reduction for the 300 mg/kg/daygroup normalized to the control group was 9%.

These results suggest that NMNadministration can significantly suppress age-associated weight gain in adose-dependent manner [10].

 

Enhances energy metabolism and supportshigher physical activity

Energy expenditure showed significantincreases in groups receiving NMN. Respiratory quotient (a value that indicateswhich macronutrients (fats, carbohydrates, or proteins) are being metabolized)significantly reduced, suggesting that NMN-administered groups switched theirmain energy source from glucose to fatty acids.

Interestingly, mice treated with NMN for 12months were able to maintain oxygen consumption and energy expenditure close tothat observed at six months in subjects without NMN. (Although an exactcomparison cannot be made, this correlates in human terms to approximately 24years’ difference between six-month and 12-month subjects). Additionally, anevaluation of whole-body movements and vertical activity showed that NMN canstimulate locomotor movement in aged mice.

These results strongly suggest that NMN hassignificant preventive effects against age-associated energy metabolismimpairment, and supports higher physical activity in aged subjects [11].

 

Improves insulin sensitivity

High insulin sensitivity allows the cellsof the body to use blood glucose more effectively, which reduces blood sugar. Researchersobserved that insulin sensitivity significantly improved in NMN-administeredmice after 12 months compared to the control group with no NMN.

In line with this improved insulinsensitivity, a key factor of insulin resistance was lower after 12 months ofNMN administration (an increase in insulin resistance with aging is one reasonwhy older adults are at higher risk of developing type 2 diabetes). Takentogether, these results highlight the ability of NMN to ameliorateage-associated decline in insulin sensitivity after long-term administration[12].

 

Holistic mitigation of other aspects ofage-associated decline

Long-term administration of NMN showedbenefits beyond the biochemical and physiological benefits mentioned above. NMNprevented age-associated gene expression changes in key metabolic organs andenhanced mitochondrial oxidative metabolism and mitonuclear protein imbalancein skeletal muscle (mitochondrial bioenergetic deterioration has been shown tobe an important factor in aging and age-related disorders such as Parkinson’sdiseases and Alzheimer’s disease [13] [14]).

Assessment of other pathophysiological changesfound that NMN brings significant anti-aging effects to a range of degradationswhich occur in both rodents and people – significantly improving aspects of eyefunction and bone density [15].

 

Well tolerated

The WUSM study demonstrated that 12 monthsof NMN administration can ameliorate aspects of age-associated physiologicaldecline without any serious side effects, providing strong evidence of thelong-term safety of NMN. Analysis of blood cell counts, blood chemistry panelsand urine did not show any sign of toxicity in research groups receiving either100 mg/kg/day or 300 mg/kg/day of NMN.

Evidence that NMN is well tolerated isfurther compounded by Seneque’s first-of-kind* OECD 408 toxicology study on NMN.Thestudy was undertaken using our high-purity form of NMN called NMN-C® (whichis commercialized as ElevantPrime NMNcapsules).

The toxicology study determined the NoObservable Adverse Effect Level (NOAEL), with results showing NMN-C® to be anexceptionally well-tolerated option in comparison to other well-known NAD+ precursorscurrently marketed to consumers.

 

The future for NMN

The pioneering WUSM paper showed for thefirst time the positive effect of NMN on a variety of physiological,biochemical, and molecular parameters during long-term administration.

Now, at Seneque, we are building on this groundbreakingresearch. Our clinical trials are assessing NMN’s effect on a range oflifespan-associated conditions, including cardiovascular, cognitive, muscular,skin and immune health.

This research will not only continue todrive NMN’s evolution as an effective anti-aging intervention in humans. Itwill also be the genesis for Senequeproducts that place advanced longevity solutions directly in the hands ofconsumers, helping people live in better health, for longer.

 

References

[1] Mills KF, Yoshida S, Stein LR, GrozioA, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, ImaiSI. Long-Term Administration of Nicotinamide Mononucleotide MitigatesAge-Associated Physiological Decline in Mice. Cell Metab. 2016 Dec 13;24(6):795-806.https://doi.org/10.1016/j.cmet.2016.09.013

[2] Ramsey, K.M., Mills, K.F., Satoh, A.and Imai, S.‐i. (2008), Age‐associated loss of Sirt1‐mediated enhancement ofglucose‐stimulated insulin secretion in beta cell‐specific Sirt1‐overexpressing(BESTO) mice. Aging Cell, 7: 78-88. https://doi.org/10.1111/j.1474-9726.2007.00355.x

[3] Revollo JR, Körner A, Mills KF, SatohA, Wang T, Garten A, Dasgupta B, Sasaki Y, Wolberger C, Townsend RR, MilbrandtJ, Kiess W, Imai S. Nampt/PBEF/Visfatin regulates insulin secretion in betacells as a systemic NAD biosynthetic enzyme. Cell Metab. 2007 Nov;6(5):363-75. https://doi.org/10.1016/j.cmet.2007.09.003 

[4] Yamamoto T, Byun J, Zhai P, Ikeda Y,Oka S, Sadoshima J. Nicotinamide mononucleotide, an intermediate of NAD+synthesis, protects the heart from ischemia and reperfusion. PLoS One. 2014 Jun6;9(6):e98972. https://doi.org/10.1371/journal.pone.0098972

[5] de Picciotto NE, Gano LB, Johnson LC,Martens CR, Sindler AL, Mills KF, Imai S, Seals DR. Nicotinamide mononucleotidesupplementation reverses vascular dysfunction and oxidative stress with agingin mice. Aging Cell. 2016 Jun;15(3):522-30. https://doi.org/10.1111/acel.12461

[6] Gomes AP, Price NL, Ling AJ, MoslehiJJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP,Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA.Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrialcommunication during aging. Cell. 2013 Dec 19;155(7):1624-38. https://doi.org/10.1016/j.cell.2013.11.037

[7] Stein LR, Imai S. Specific ablation ofNampt in adult neural stem cells recapitulates their functional defects duringaging. EMBO J. 2014 Jun 17;33(12):1321-40. https://doi.org/10.1002/embj.201386917

[8] Long AN, Owens K, Schlappal AE,Kristian T, Fishman PS, Schuh RA. Effect of nicotinamide mononucleotide onbrain mitochondrial respiratory deficits in an Alzheimer's disease-relevantmurine model. BMC Neurol. 2015 Mar 1;15:19. https://doi.org/10.1186/s12883-015-0272-x

[9] Wang X, Hu X, Yang Y, Takata T, SakuraiT. Nicotinamide mononucleotide protects against β-amyloid oligomer-inducedcognitive impairment and neuronal death. Brain Res. 2016 Jul 15;1643:1-9. https://doi.org/10.1016/j.brainres.2016.04.060

[10] Mills KF, Yoshida S, Stein LR, GrozioA, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, ImaiSI. Long-Term Administration of Nicotinamide Mononucleotide MitigatesAge-Associated Physiological Decline in Mice. Cell Metab. 2016 Dec13;24(6):795-806. https://doi.org/10.1016/j.cmet.2016.09.013

[11] Mills KF, Yoshida S, Stein LR, GrozioA, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, ImaiSI. Long-Term Administration of Nicotinamide Mononucleotide MitigatesAge-Associated Physiological Decline in Mice. Cell Metab. 2016 Dec13;24(6):795-806. https://doi.org/10.1016/j.cmet.2016.09.013

[12] Mills KF, Yoshida S, Stein LR, GrozioA, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, ImaiSI. Long-Term Administration of Nicotinamide Mononucleotide MitigatesAge-Associated Physiological Decline in Mice. Cell Metab. 2016 Dec13;24(6):795-806. https://doi.org/10.1016/j.cmet.2016.09.013

[13] Natarajan V, Chawla R, Mah T,Vivekanandan R, Tan SY, Sato PY, Mallilankaraman K. Mitochondrial Dysfunctionin Age-Related Metabolic Disorders. Proteomics. 2020 Mar;20(5-6):e1800404. doi:10.1002/pmic.201800404. Epub 2020 Mar 17. PMID: 32131138. https://doi.org/10.1002/pmic.201800404

[14] Srivastava S. The Mitochondrial Basisof Aging and Age-Related Disorders. Genes (Basel). 2017 Dec 19;8(12):398. doi:10.3390/genes8120398. PMID: 29257072; PMCID: PMC5748716. https://doi.org/10.3390/genes8120398

[15] Mills KF, Yoshida S, Stein LR, GrozioA, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, ImaiSI. Long-Term Administration of Nicotinamide Mononucleotide MitigatesAge-Associated Physiological Decline in Mice. Cell Metab. 2016 Dec13;24(6):795-806. https://doi.org/10.1016/j.cmet.2016.09.013

*Statement based on review of publicationson PubMed as of January 1, 2021

News
January 7, 2019

NMN enters cells via a specific NMN transporter
One of the properties that makes NMN such a highly promising molecule is its potential speed of absorption into the body. Seneque Chief Scientist Dr. Alessia Grozio was part of a team that in 2019 published groundbreaking research which highlighted a key driver of NMN’s efficiency – a transporter that carries NMN directly into cells [1] within ten minutes of ingestion.

Until then, research had shown that increasing NAD+ levels through treatment with metabolic precursors extends lifespan in yeast and, in aged mice, improves motor coordination, eye function, bone density, insulin sensitivity, liver and kidney function, physical endurance, muscle strength, and the function of stem cells and mitochondria [2] [3].

But the question of how mammals absorb and manufacture NAD+ had not been fully resolved.
Dr. Grozio and the team showed that the Slc12a8 gene encodes a protein that is a specific NMN transporter in mammals.

This protein uses a sodium ion to transport NMN (but not nicotinamide riboside (NR) [4]) across cell membranes and facilitates direct uptake of NMN into the gut and other organs. There, it is immediately used for NAD+ biosynthesis and significantly increases NAD+ concentration in cells over the course of 60 minutes following ingestion [5].

Previously, NMN was known to enter cells by the removal of a phosphate group which turned it into NR. In this form, it was carried through the cell membrane by equilibrative nucleotide transporters and, once inside the cell, re-phosphorylated back into NMN [6].

To test the existence of a specific NMN transporter, the scientists inhibited cellular pathways that NR uses to enter liver cells. They observed that NMN levels increased with NMN administration, despite the inhibition of NR uptake, confirming the presence of a specific NMN transporter facilitating NMN movement into cells. Conversely, rapid cellular uptake of NMN to cells was lost when the scientists decreased levels of Slc12a8 [7].

Slc12a8 is highly expressed in the small intestine of mice (related transporters exist in other organisms – including humans – so it is possible for us to have these NMN transporters in the gut). Its expression increases in the intestines of old mice as NAD+ levels decline, which suggests that this may be a function designed to compensate for the degradation and decline of NAD+ that accompanies the aging process [8].

The identification and characterization of the Slc12a8 NMN transporter significantly enhanced our understanding of how mammals absorb and manufacture NAD+. It has opened the door to ever-more effective methods of NMN administration, which we are exploring at Seneque with Dr Grozio and other NAD+ experts through our clinical research pipeline.

You can access a free version of the full article Slc12a8 is a nicotinamide mononucleotide transporter here:

References
[1] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[2] Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D'Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016 Jun 17;352(6292):1436-43. https://doi.org/10.1126/science.aaf2693
[3] Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016 Dec 13;24(6):795-806. https://doi.org/10.1016/j.cmet.2016.09.013
[4] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[5] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[6] Ratajczak J, Joffraud M, Trammell SA, Ras R, Canela N, Boutant M, Kulkarni SS, Rodrigues M, Redpath P, Migaud ME, Auwerx J, Yanes O, Brenner C, Cantó C. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun. 2016 Oct 11;7:13103. https://doi.org/10.1038/ncomms13103
[7] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[8] Schultz MB, Sinclair DA. Why NAD(+) Declines during Aging: It's Destroyed. Cell Metab. 2016 Jun 14;23(6):965-966. https://doi.org/10.1016/j.cmet.2016.05.022