Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans. Nicotinamide adenine dinucleotide (NAD+) is a central redox factor and enzymatic cofactor that functions in a plethora of cellular processes, including metabolic pathways and DNA metabolism, and affects cell fate and function. NAD+ levels gradually decline with age, and therapeutic elevation of NAD+ levels is being trialled for extending human healthspan and lifespan.

NAD+ metabolism and its roles in cellular processes during ageing

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.

Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages.

Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.

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The metabolic roots of senescence: mechanisms and opportunities for intervention.

Cellular senescence and senolytics: the path to the clinic

Evolving concepts in NAD+ metabolism.

Decreased NAD+ levels have been shown to contribute to metabolic dysfunction during aging. NAD+ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD+ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38+ immune cells. Inflammation increases CD38 and decreases NAD+. In addition, senescent cells and their secreted signals promote accumulation of CD38+ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD+ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD+ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD+.

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels.

In this issue of Public HealthNutrition, Smilie et al.(1) dare to challenge the adequacy of the refeeding regimen in the WHO’s time-tested, data-driven, health-enhancing, lifesaving Ten Steps programme for themanagement of severe acutemalnutrition (SAM). Bravely, they trample on the central tenets of the ‘holy grail’ of malnutrition management. Are they justified? One could claim that there were three ‘top’ public health developments during the 20th Century – vaccines, antibiotics and oral rehydration solutions. With malnutrition contributing to nearly half of childhood deaths around the planet, the release of the WHO’s Ten Steps programme for SAM in 1999 markedly reduced the morbidity and mortality associated with childhood malnutrition, perhaps qualifying it as the top public health nutrition intervention of the current century. These Ten Steps allow an algorithmic scheme to take even highly trained physicians away from complex management thoughts to simply focus on stepwise interventions to save lives and restore health(2,3). Popular wisdom tells us not to change processes that are already working: ‘If it ain’t broke, don’t fix it’. Obviously, unbroken vaccination and antibiotic therapies have been improved with subsequent additions and changes to regimens. Even the simple and effective ‘magic bullet’ of oral rehydration therapy for combatting diarrhoeal dehydration was subjected to decades of revisions with changes in sugar source and osmolar concentration(4,5). As vaccines, antibiotics and oral rehydration solutions have been improved (without being totally broken), somalnutrition management can be improved. Specifically, theWHOpredicts<10%mortality in children with complicated SAM treated based on the Ten Step recommendations. However, despite guideline compliance, some sub-Saharan Africa hospitals report 10–40% mortality in hospitalised childrenwith SAM(6). This lowered rate ofmorbidity andmortality may be further reducedwith updates based on recent research. To clarify, of the thirty-three WHO recommendations for managing SAM, only eleven are based on directly relevant research, while sixteen are based solely on expert opinion and six are based either on studies not conducted in children with complicated SAM or using non-identical treatment recommendations. Furthermore, the recommendations for micronutrient supplementation are almost solely based onexpert opinionwith the exception of the vitaminA recommendations that came from the results of three randomised controlled trials(6). It has already been suggested that refeeding programmes should include better thiamine delivery to children, and there are new data suggesting that longterm recovery from SAM could be enhanced by using foods that consider growth-promoting patterns in the local population’smicrobiome(7,8). Now, Smilie et al.(1) show that current malnutrition management is ‘broken’ in regards to Ca and vitamin D nutrition, and they suggest ‘fixes’. SAM, defined as having a weight-for-height z-score <−3, a mid-upper arm circumference of <115 mm or bilateral oedema, is sometimes associated with Ca deficiency and increases the risks of rickets and hypocalcaemia(2). Despite this potential link, few studies have examined the serum Ca levels in children hospitalised with SAM. Smilie et al.(1) help fill this gap. Their analysis of 150 patients aged 1–59 months, who were hospitalised with SAM in a Delhi tertiary hospital, found that 26% had hypocalcaemia (<2·12 mmol/l), 65·3% had vitamin D deficiency (serum 25-(OH)D< 30 nmol/l) and 42% had clinical rickets. Importantly, hypocalcaemia occurred more commonly in patients with clinical rickets (OR= 6·6), suggesting an increased vulnerability in patients already displaying signs of decreased Ca and/or vitamin D reserve. These results highlight a couple of significant outcomes of Ca and vitamin D deficiency. First, although rickets is common inmany parts of theworld(9,10), Smilie et al.(1) finding that 42% of their malnourished children had rickets is alarming. Furthermore, the fact that even more children had deficient circulating levels of vitamin D and Ca, the nutritional elements essential for bone health and the prevention of rickets, gives added reason for concern. Rickets is the tip of the proverbial iceberg of otherwise hidden derangements in Ca and vitamin D homoeostasis. Rickets is clinically significant as it is associated with skeletal deformities, dental abnormalities, bone pain, muscle weakness, failure to thrive, developmental delay, hypocalcaemic seizures and, sometimes, even death from complications of hypocalcaemia(9–12). Separate from renal disease and hereditary syndromes, nutritional rickets results from isolated and/or interacting deficiencies of Ca and vitamin D as adequate Ca is not delivered to, deposited in and maintained in bones(9,10,13). Public Health Nutrition: 23(17), 3187–3189 doi:10.1017/S1368980020002499

Severe acute malnutrition, calcium and vitamin D: important interactions.

ABSTRACT: Background: When adolescents present with symptoms of unexplained weight loss, underweight, or poor appetite, eating disorders (EDs) are commonly on the list of differential diagnoses. However, the relationship of these symptoms to other psychiatric disorders is often less clear. Methods: Using the Rochester Epidemiology Project database, a retrospective cohort study of adolescents (13–18 years) with billing diagnoses of weight loss, underweight, or loss of appetite was conducted between January 2005 and December 2017. Patients who presented with conditions commonly associated with weight loss, underweight, or poor appetite (e.g., cancer) were excluded. This study sought to examine the proportion of patients who received ED and psychiatric diagnoses within 5 years of the index visit and patient characteristics associated with these diagnoses. Results: Of 884 patients diagnosed with symptoms of unexplained weight loss, underweight, or poor appetite, 662 patients (M age = 15.8; SD = 1.6; 66.0% female) met study criteria. Within 5 years of the index visit, the lifetime prevalence of all psychiatric disorders was 70% (n = 461) and of EDs was 21% (n = 141). For both psychiatric disorders and EDs, sex and race were significantly associated with receiving a diagnosis within 5 years. Decrease in body mass index (BMI) percentile was associated with receiving an ED diagnosis, whereas the highest historical BMI percentile was associated with receiving a psychiatric diagnosis. Conclusion: Patients presenting with symptoms of unexplained weight loss, underweight, or poor appetite are at risk not only for EDs but also for other psychiatric disorders that may require further assessment and follow-up.

Micaela A. Witte

Papers

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels.

Severe acute malnutrition, calcium and vitamin D: important interactions.

Lifetime Prevalence of Psychiatric Disorders in Adolescents with Unexplained Weight Loss, Underweight, or Poor Appetite