BackgroundThe level of body-mass index (BMI) associated with the lowest risk of death remains unclear. Although differences in muscle mass limit the utility of BMI as a measure of adiposity, no study has directly examined the effect of muscle mass on the BMI-mortality relationship.MethodsBody composition was measured by dual-energy x-ray absorptiometry in 11,687 participants of the National Health and Nutrition Examination Survey 1999–2004. Low muscle mass was defined using sex-specific thresholds of the appendicular skeletal muscle mass index (ASMI). Proportional hazards models were created to model associations with all-cause mortality.ResultsAt any level of BMI ≥22, participants with low muscle mass had higher body fat percentage (%TBF), an increased likelihood of diabetes, and higher adjusted mortality than other participants. Increases in %TBF manifested as 30–40% smaller changes in BMI than were observed in participants with preserved muscle mass. Excluding participants with low muscle mass or adjustment for ASMI attenuated the risk associated with low BMI, magnified the risk associated with high BMI, and shifted downward the level of BMI associated with the lowest risk of death. Higher ASMI was independently associated with lower mortality. Effects were similar in never-smokers and ever-smokers. Additional adjustment for waist circumference eliminated the risk associated with higher BMI. Results were unchanged after excluding unintentional weight loss, chronic illness, early mortality, and participants performing muscle-strengthening exercises or recommended levels of physical activity.ConclusionsMuscle mass mediates associations of BMI with adiposity and mortality and is inversely associated with the risk of death. After accounting for muscle mass, the BMI associated with the greatest survival shifts downward toward the normal range. These results provide a concrete explanation for the obesity paradox.

Background and objectives Muscle wasting is common among patients with ESRD, but little is known about differences in muscle mass in persons with CKD before the initiation of dialysis. If sarcopenia was common, it might affect the use of body mass index for diagnosing obesity in people with CKD. Because obesity may be protective in patients with CKD and ESRD, an accurate understanding of how sarcopenia affects its measurement is crucial.Design, setting, participants, & measurements Differences in body composition across eGFR categories in adult participants of the National Health and Nutrition Examination Survey 1999-2004 who underwent dual-energy x-ray absorptiometry were examined. Obesity defined by dual-energy x-ray absorptiometry versus body mass index and sarcopenia as a contributor to misclassification by body mass index were examined.Results Sarcopenia and sarcopenic obesity were more prevalent among persons with lower eGFR (P trend ,0.01 and P trend ,0.001, respectively). After multivariable adjustment, the association of sarcopenia with eGFR was U-shaped. Stage 4 CKD was independently associated with sarcopenia among participants $60 years old (adjusted odds ratio, 2.58; 95% confidence interval, 1.02 to 6.51 for eGFR=15-29 compared with 60-89 ml/min per 1.73 m 2 ; P for interaction by age=0.02). Underestimation of obesity by body mass index compared with dualenergy x-ray absorptiometry increased with lower eGFR (P trend ,0.001), was greatest among participants with eGFR=15-29 ml/min per 1.73 m 2 (71% obese by dual-energy x-ray absorptiometry versus 41% obese by body mass index), and was highly likely among obese participants with sarcopenia (97.7% misclassified as not obese by body mass index).Conclusions Sarcopenia and sarcopenic obesity are highly prevalent among persons with CKD and contribute to poor classification of obesity by body mass index. Measurements of body composition beyond body mass index should be used whenever possible in the CKD population given this clear limitation.

Introduction In pre-dialysis chronic kidney disease (CKD), the association of muscle mass with mortality is poorly defined, and no study has examined outcomes related to the co-occurrence of low muscle mass and excess adiposity (sarcopenic-obesity). Methods: We examined abnormalities of muscle and fat mass in adult participants of the National Health and Nutrition Examination Survey 1999–2004. We determined whether associations of body composition with all-cause mortality differed between participants with CKD compared to those without. Results CKD modified the association of body composition with mortality (p=0.01 for interaction). In participants without CKD, both sarcopenia and sarcopenic obesity were independently associated with increased mortality compared with normal body composition (hazard ratio (HR) 1.44 (95%CI 1.07–1.93) and 1.64 (95%CI 1.26–2.13), respectively). These associations were not present among participants with CKD. Conversely, obese persons had the lowest adjusted risk of death, with an increased risk among those with sarcopenia (HR 1.43 (95%CI 1.05–1.95)) but not sarcopenic-obesity (p=0.003 for interaction by CKD status; HR 1.21 (95%CI 0.89–1.65)), compared with obesity. Conclusion Sarcopenia associates with increased mortality regardless of eGFR, but excess adiposity modifies this association among people with CKD. Future studies of prognosis and weight loss and exercise interventions in CKD patients should consider muscle mass and adiposity together rather than in isolation.

Nicotinamide adenine dinucleotide (NADNicotinamide adenine dinucleotide (NAD ϩ ) is an essential redox molecule and a key player in several signaling pathways that govern fundamental biological processes (1, 2). In the redox reactions, a hydride equivalent is reversibly transferred at the nicotinamide moiety, resulting in a switch between oxidized (NAD ϩ ) and reduced (NADH) forms of the nucleotide. Although the redox reactions are critical for efficient mitochondrial metabolism, they are not accompanied by any net consumption of the nucleotide. On the contrary, NAD ϩ -dependent signaling processes lead to its degradation.Three distinct families of enzymes consume NAD ϩ as substrate: poly(ADP-ribose) polymerases (PARPs), 2 ADP-ribosyl cyclases (CD38 and CD157), and sirtuins (SIRT1-7) (3-5). PARPs hydrolyze NAD ϩ and transfer the ADP-ribose moiety of NAD ϩ to a receptor amino acid, building poly(ADP-ribose) polymers. PARPs regulate DNA damage repair, tumorigenesis, cell differentiation, and metabolism (3, 6, 7). CD38 is a ubiquitously expressed multifunctional enzyme that catalyzes the production of second messengers (like cyclic ADP-ribose) (8), which act as potent intracellular calcium-mobilizing agents to control cell cycle, insulin signaling, and microglial activation (8 -10). Sirtuins are a highly conserved family of proteins capable of catalyzing NAD ϩ -dependent deacylation and mono-(ADP-ribosyl)ation reactions (11). Sirtuin activation has been shown to modulate mitochondrial biogenesis and all major mitochondrial processes, including the tricarboxylic acid cycle, fatty acid metabolism, oxidative phosphorylation, and antioxidant response (4,(12)(13)(14)(15). Because all of the above NAD ϩ -consuming enzymes generate nicotinamide (NAM) as a byproduct, mammalian cells have evolved an NAD ϩ salvage pathway capable of resynthesizing NAD ϩ from NAM (16). Although NAD ϩ synthesis can occur from L-tryptophan (kynurenine pathway), nicotinic acid (Preiss-Handler pathway), or nicotinamide riboside (NR) (17-19), the salvage pathway appears to account for the majority of NAD ϩ synthesis in mammalian cells. The enzyme nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the conversion of NAM and 5Ј-phosphoribosyl 1-pyrophosphate to nicotinamide mononucleotide (NMN); subsequently nicotinamide mononucleotide * This study was supported by National Institutes of Health Grants NS089640 and GM103542. The authors declare that they have no conflict of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 20,21). NAMPT is the rate-limiting enzyme in this pathway. Accordingly, overexpression of NAMPT, but not NMNATs, increases NAD levels (22-24).adenylyltransferases (NMNATs) transfer adenine from ATP to NMN to generate NAD ϩ (All the different types of NAD ϩ -consuming reactions have been described in the mitochondria, but in general NAMPT appears to be absent from the mitochondrial compartment (22, 24 -26), and the ori...