Dr. Weeks Comment: We in the orthomolecular medicine camp – indebted as we are to Abram Hoffer, PhD MD (the father of orthomolecular medicine and teacher of Linus Pauling PhD re vitamin C) –  have known that niacin (vitamin B3) and niacinamide (another version of B3) help people live longer and live healthier.    Today, Dr. David Sinclair – named by Time Magazine as one of the most influential scientists alive today (based on his anti-aging work with NMN) is the newest champion of the vitamin B3 family and its related anti-aging gene SIRT1.   So take your niacin and also take your SOUL since this whole crushed seed drink stimulates the anti-aging SIRT1 gene 62%.   Read about Dr. Sinclair’s research below. 

“… that activation of SIRT1 has potential as a therapeutic approach to protect the heart against ER stress-induced injury.”

“… NAD(+) is required not only for life but for a long life…”

My thanks to my brilliant colleague Dr. Bruce Rind (www.drrind.com) for sending me this link for my consideration. 

 

 

Metab Syndr Relat Disord. 2017 Feb;15(1):4-5. doi: 10.1089/met.2017.0004. Epub 2017 Feb 6.

Response to: “If the Metabolic Winter Is Coming, When Will It Be Summer?” (Metab Syndr Relat Disord 2017;15:3).

Cronise RJ1, Sinclair DA2,3, Bremer AA4.

 

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Cell Death Differ. 2017 Feb;24(2):343-356. doi: 10.1038/cdd.2016.138. Epub 2016 Dec 2.

SIRT1 protects the heart from ER stress-induced cell death through eIF2α deacetylation.

Prola A1, Silva JP1, Guilbert A1, Lecru L2, Piquereau J1, Ribeiro M1, Mateo P1, Gressette M1, Fortin D1, Boursier C3, Gallerne C2, Caillard A4, Samuel JL4, François H2, Sinclair DA5,6, Eid P2, Ventura-Clapier R1, Garnier A1, Lemaire C1,7.

 

 

Abstract

Over the past decade, endoplasmic reticulum (ER) stress has emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. Cardiac therapy based on ER stress modulation is viewed as a promising avenue toward effective therapies for the diseased heart. Here, we tested whether sirtuin-1 (SIRT1), a NAD+-dependent deacetylase, participates in modulating ER stress response in the heart. Using cardiomyocytes and adult-inducible SIRT1 knockout mice, we demonstrate that SIRT1 inhibition or deficiency increases ER stress-induced cardiac injury, whereas activation of SIRT1 by the SIRT1-activating compound STAC-3 is protective. Analysis of the expression of markers of the three main branches of the unfolded protein response (i.e., PERK/eIF2α, ATF6 and IRE1) showed that SIRT1 protects cardiomyocytes from ER stress-induced apoptosis by attenuating PERK/eIF2α pathway activation. We also present evidence that SIRT1 physically interacts with and deacetylates eIF2α. Mass spectrometry analysis identified lysines K141 and K143 as the acetylation sites on eIF2α targeted by SIRT1. Furthermore, mutation of K143 to arginine to mimic eIF2α deacetylation confers protection against ER stress-induced apoptosis. Collectively, our findings indicate that eIF2α deacetylation on lysine K143 by SIRT1 is a novel regulatory mechanism for protecting cardiac cells from ER stress and suggest that activation of SIRT1 has potential as a therapeutic approach to protect the heart against ER stress-induced injury.

 

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Nat Rev Mol Cell Biol. 2016 Nov;17(11):679-690. doi: 10.1038/nrm.2016.93. Epub 2016 Aug 24.

Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds.

Bonkowski MS1, Sinclair DA1,2.

Abstract

The sirtuins (SIRT1-7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with sirtuin-activating compounds (STACs) such as resveratrol and SRT2104 or with NAD+ precursors, have improved organ function, physical endurance, disease resistance and longevity. Trials in non-human primates and in humans have indicated that STACs may be safe and effective in treating inflammatory and metabolic disorders, among others. These advances have demonstrated that it is possible to rationally design molecules that can alleviate multiple diseases and possibly extend lifespan in humans.

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Cell Metab. 2016 Oct 11;24(4):566-581. doi: 10.1016/j.cmet.2016.09.004.

NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair.

Fang EF1, Kassahun H2, Croteau DL1, Scheibye-Knudsen M3, Marosi K4, Lu H1, Shamanna RA1, Kalyanasundaram S5, Bollineni RC6, Wilson MA4, Iser WB4, Wollman BN1, Morevati M3, Li J7, Kerr JS1, Lu Q1, Waltz TB1, Tian J1, Sinclair DA8, Mattson MP9, Nilsen H2, Bohr VA10.

Abstract

Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.

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Front Pharmacol. 2016 Aug 19;7:258. doi: 10.3389/fphar.2016.00258. eCollection 2016.

Head to Head Comparison of Short-Term Treatment with the NAD(+) Precursor Nicotinamide Mononucleotide (NMN) and 6 Weeks of Exercise in Obese Female Mice.

Uddin GM1, Youngson NA1, Sinclair DA2, Morris MJ1. 

 

Abstract

Obesity is well known to be a major cause of several chronic metabolic diseases, which can be partially counteracted by exercise. This is due, in part, to an upregulation of mitochondrial activity through increased nicotinamide adenine dinucleotide (NAD(+)). Recent studies have shown that NAD(+) levels can be increased by using the NAD(+) precursor, nicotinamide mononucleotide (NMN) leading to the suggestion that NMN could be a useful intervention in diet related metabolic disorders. In this study we compared the metabolic, and especially mitochondrial-associated, effects of exercise and NMN in ameliorating the consequences of high-fat diet (HFD) induced obesity in mice. Sixty female 5 week old C57BL6/J mice were allocated across five groups: Chow sedentary: CS; Chow exercise: CEX; HFD sedentary: HS; HFD NMN: HNMN; HFD exercise: HEX (12/group). After 6 weeks of diet, exercise groups underwent treadmill exercise (15 m/min for 45 min), 6 days per week for 6 weeks. NMN or vehicle (500 mg/kg body weight) was injected (i.p.) daily for the last 17 days. No significant alteration in body weight was observed in response to exercise or NMN. The HFD significantly altered adiposity, glucose tolerance, plasma insulin, NADH levels and citrate synthase activity in muscle and liver. HEX and HNMN groups both showed significantly improved glucose tolerance compared to the HS group. NAD(+) levels were increased significantly both in muscle and liver by NMN whereas exercise increased NAD(+) only in muscle. Both NMN and exercise ameliorated the HFD-induced reduction in liver citrate synthase activity. However, exercise, but not NMN, ameliorated citrate synthase activity in muscle. Overall these data suggest that while exercise and NMN-supplementation can induce similar reversal of the glucose intolerance induced by obesity, they are associated with tissue-specific effects and differential alterations to mitochondrial function in muscle and liver.

 

 

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Methods Enzymol. 2016;574:213-44. doi: 10.1016/bs.mie.2016.01.012. Epub 2016 Feb 9.

Synthesis and Assay of SIRT1-Activating Compounds.

Dai H1, Ellis JL1, Sinclair DA2, Hubbard BP3.

 

Abstract

The NAD(+)-dependent deacetylase SIRT1 plays key roles in numerous cellular processes including DNA repair, gene transcription, cell differentiation, and metabolism. Overexpression of SIRT1 protects against a number of age-related diseases including diabetes, cancer, and Alzheimer’s disease. Moreover, overexpression of SIRT1 in the murine brain extends lifespan. A number of small-molecule sirtuin-activating compounds (STACs) that increase SIRT1 activity in vitro and in cells have been developed. While the mechanism for how these compounds act on SIRT1 was once controversial, it is becoming increasingly clear that they directly interact with SIRT1 and enhance its activity through an allosteric mechanism. Here, we present detailed chemical syntheses for four STACs, each from a distinct structural class. Also, we provide a general protocol for purifying active SIRT1 enzyme and outline two complementary enzymatic assays for characterizing the effects of STACs and similar compounds on SIRT1 activity.

 

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Cell Res. 2016 Sep;26(9):971-2. doi: 10.1038/cr.2016.80. Epub 2016 Jun 24.

Restoring stem cells – all you need is NAD(.).

Wu LE1, Sinclair DA1,2.

 

Abstract

The loss of stem cells, through cell dysfunction or senescence, is thought to contribute to biological aging. Recently, Hongbo Zhang and colleagues have shown that activation of the mitochondrial unfolded protein response, a retrograde stress response, through administration with an NAD-raising compound, can rejuvenate stem cells and extend lifespan in mice.

 

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Cell Metab. 2016 Jun 14;23(6):1093-112. doi: 10.1016/j.cmet.2016.05.027.

Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.

Mitchell SJ1, Madrigal-Matute J2, Scheibye-Knudsen M3, Fang E4, Aon M5, González-Reyes JA6, Cortassa S5, Kaushik S2, Gonzalez-Freire M1, Patel B2, Wahl D1, Ali A1, Calvo-Rubio M6, Burón MI6, Guiterrez V1, Ward TM1, Palacios HH1, Cai H7, Frederick DW8, Hine C9, Broeskamp F10, Habering L10, Dawson J11, Beasley TM11, Wan J12, Ikeno Y13, Hubbard G13, Becker KG14, Zhang Y14, Bohr VA4, Longo DL14, Navas P15, Ferrucci L1, Sinclair DA16, Cohen P12, Egan JM7, Mitchell JR9, Baur JA8, Allison DB11, Anson RM1, Villalba JM6, Madeo F10, Cuervo AM2, Pearson KJ17, Ingram DK18, Bernier M1, de Cabo R19.

 

Abstract

Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.

 

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Cell Metab. 2016 Jun 14;23(6):965-6. doi: 10.1016/j.cmet.2016.05.022.

Why NAD(+) Declines during Aging: It’s Destroyed.

Schultz MB1, Sinclair DA2.

 

Abstract

NAD(+) is required not only for life but for a long life. In this issue, Camacho-Pereira et al. (2016) implicate CD38 in the decline of NAD(+) during aging, with implications for combating age-related diseases.

 

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Development. 2016 Jan 1;143(1):3-14. doi: 10.1242/dev.130633.

When stem cells grow old: phenotypes and mechanisms of stem cell aging.

Schultz MB1, Sinclair DA2.

 

Abstract

All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan.