Boosting NAD+ improves muscle disease


NAD+ is a redox-active metabolite, the depletion of which has been proposed to promote aging and degenerative diseases in rodents. However, whether NAD+ depletion occurs in patients with degenerative disorders and whether NAD+ repletion improves their symptoms has remained open.

Here, we report systemic NAD+ deficiency in adult-onset mitochondrial myopathy patients. We administered an increasing dose of NAD+-booster niacin, a vitamin B3 form (to 750-1,000 mg/day; NCT03973203) for patients and their matched controls for 10 or 4 months, respectively.

Blood NAD+ increased in all subjects, up to 8-fold, and muscle NAD+ of patients reached the level of their controls. Some patients showed anemia tendency, while muscle strength and mitochondrial biogenesis increased in all subjects. In patients, muscle metabolome shifted toward controls and liver fat decreased even 50%.

Our evidence indicates that blood analysis is useful in identifying NAD+ deficiency and points niacin to be an efficient NAD+ booster for treating mitochondrial myopathy.

SOURCE: Cell Metabolism

EDITOR’S NOTE: Increased blood levels of NAD+ were achieved here with a readily available supplement, niacin (vitamin B3).

Calorie restriction


Nutrient and stress sensors mediate lifespan extensions that occur in response to many different environmental and physiological signals. The best known of these signals is dietary restriction, which extends lifespan in many species, from yeast to primates.

Dietary restriction was initially assumed to extend lifespan simply by reducing the rate at which cellular damage accumulates over time as a result of nutrient metabolism. Recently, however, an elegant experiment with Drosophila showed that dietary restriction produces a rapid decrease in the mortality rate (the daily chance of death), suggesting that dietary restriction counteracts the causes of ageing in an acute manner.

We now know that the longevity response to dietary restriction is actively regulated by nutrient-sensing pathways involving the kinase target of rapamycin (TOR), AMP kinase, sirtuins and insulin/insulin-like growth factor (IGF-1) signalling.

Unexpectedly, which nutrient sensor is most important in extending lifespan in response to dietary restriction depends on the way that dietary restriction is imposed. In C. elegans, for example, one nutrient sensor extends lifespan in response to life-long food limitation, another in response to every-other-day feeding and a third if dietary restriction begins in middle age.

SOURCE: Nature (2010)

NAD deficiency + niacin supplementation


Background: Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients.

Methods: We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system.

Results: Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects.

Conclusions: Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice.


EDITOR’S NOTE: Apparent restoration of NAD synthesis was achieved here with a readily available supplement, niacin (vitamin B3).

Biomarkers of aging


The aging process results in multiple traceable footprints, which can be quantified and used to estimate an organism’s age. Examples of such aging biomarkers include epigenetic changes, telomere attrition, and alterations in gene expression and metabolite concentrations.

More than a dozen aging clocks use molecular features to predict an organism’s age, each of them utilizing different data types and training procedures. Here, we offer a detailed comparison of existing mouse and human aging clocks, discuss their technological limitations and the underlying machine learning algorithms.

We also discuss promising future directions of research in biohorology — the science of measuring the passage of time in living systems. Overall, we expect deep learning, deep neural networks and generative approaches to be the next power tools in this timely and actively developing field.

FULL TEXT: Ageing Research Reviews