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A study reporting an upregulation of CD38+ expression with age as the sole major age-related move amongst the players involved in NAD+ levels (NAMPT, PARP1, SIRT1) got a lot of attention here (starting in 2015 and then in 2016 in the omnibus thread), along with drugs and (hyped) supplements to inhibit it — despite the risks of inhibiting CD38 (bacterial infection and suppression of ACTH and oxytocin secretion, leading to impaired maternal nurturing and social behhavior). Recently, two groups have separately found evidence that the age-related rise in CD38 expression is driven by the secretory phenotype of senescent cells (SASP), which increases its expression in adipose macrophages: this opens up a solution based on repair of cellular and molecular damage rather than messing with metabolism: ablate the senescent cells, and CD38+ expression and macrophage polarization should normalize. Indeed, the downstream effects on macrophage polarization and NAD+ consumption now seem likely responsible for a significant amount of the remarkably sweeping effects of senolytic therapies.
But most studies find to the contrary that all the players, with the exception of SIRT1 (where the data are inconsistent) move in a direction that leads toward lower NAD+ levels — as, in fact, the principal investigator (Eduardo Chini) and members of his lab acknowledge in PMID 27825999 (a nice review that really gets into the weeds on a lot of issues). And of course, nearly all of those data are in mice.
Here, the authors not only confirm a relatively early (age 55) decline in NAMPT protein levels in skeletal muscle, but show that aerobic exercise or resistance training both boost NAMPT protein levels, with a disproportionate effect in older vs. younger subjects:
de Guia RM, Agerholm M, Nielsen TS, Consitt LA, Søgaard D, Helge JW, Larsen S, Brandauer J, Houmard JA, Treebak JT.
Aerobic and resistance exercise training reverses age-dependent decline in NAD(+) salvage capacity in human skeletal muscle.
Physiol Rep. 2019 Jul;7(12):e14139. doi: 10.14814/phy2.14139. PubMed PMID: 31207144.
... In skeletal muscle, NAD+ is mainly generated by the NAD+ salvage pathway in which nicotinamide phosphoribosyltransferase (NAMPT) is rate‐limiting. NAMPT decreases with age in human skeletal muscle, and aerobic exercise training increases NAMPT levels in young men. However, whether distinct modes of exercise training increase NAMPT levels in both young and old people is unknown.
We assessed the effects of 12 weeks of aerobic and resistance exercise training ...in young (≤35 years) and older (≥55 years) individuals. NAMPT in skeletal muscle correlated negatively with age (r2 = 0.297, P < 0.001, n = 57) [and with other drivers and consequences of metabolic abnormality:
VO2peak was the best predictor of NAMPT levels.
Moreover, aerobic exercise training increased NAMPT abundance 12% and 28% in young and older individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively. None of the other proteins changed with exercise training.
In a separate cohort of young and old people, levels of NAMPT, NRK1, and NMNAT1/2 in abdominal subcutaneous adipose tissue were not affected by either age or 6 weeks of high‐intensity interval training. ... However, the positive effects of exercise training on adipose tissue may be depot‐specific. Visceral and subcutaneous adipose tissues show varying degrees of insulin resistance during obesity and type 2 diabetes (Bonora 2000; Frayn 2000; Hsieh et al. 2014). A study of 16 obese subjects who underwent Roux‐en‐Y gastric bypass surgery, provided evidence of similar NAMPT protein levels in subcutaneous adipose tissue of insulin‐sensitive and insulin‐resistant subjects (Xu et al. 2012). However, significant differences were observed in NAMPT levels of visceral fat depots (Xu et al. 2012). In a separate study with obese and non‐obese individuals, NAMPT mRNA levels were unaltered in subcutaneous adipose tissue depots (Chang et al. 2010). ...
While skeletal muscle NAMPT levels correlated with age, BMI, body fat percentage, VO2peak and lean body mass, none of these parameters correlated significantly with eNAMPT [ie, extracellular NAMPT, a somewhat controversial protein with reports of positive (hypothalamic NAD+, physical activity) and negative (inflammation, cancer) effects -MR]. Nevertheless, eNAMPT levels showed weak, but significant, negative correlations with fasting plasma glucose (r2 = 0.2122, P < 0.01; Fig. 4A) and HOMA‐IR (r2 = 0.163, P < 0.05; Fig. 4C) and a marginal correlation with fasting insulin (r2 = 0.141, P = 0.0525; Fig. 4B). Plasma eNAMPT levels were unaltered by exercise training (Fig. 4D–E).
... Given the role of NAMPT for maintaining the functional capacity (e.g., contractility and oxidative respiration) of skeletal muscle (Frederick et al. 2016; Agerholm et al. 2018), our findings highlight the importance of exercise training as an effective intervention to prevent aging‐associated declines in skeletal muscle function. Lifelong (>10 years) football training, which consists of a combination of aerobic and resistance training, increases NAMPT, TFAM and PGC1α mRNA levels in skeletal muscle (Mancini et al. 2017) highlighting the possible involvement of the NAD+ salvage pathway for exercise training‐induced improvements in mitochondrial function (Alfieri et al. 2015). This link is further supported by findings of increased SIRT3 levels in response to exercise training (Johnson et al. 2015). ...
the mechanism by which exercise training promotes NAMPT abundance in skeletal muscle is unclear. Our previous work suggested that AMPK controls NAMPT levels in mouse skeletal muscle through a posttranscriptional mechanism (Brandauer et al. 2013). However, the Nampt promoter is regulated by the circadian core clock machinery (Ramsey et al. 2009) and SIRT1 (Nakahata et al. 2009), and exercise alters mRNA expression of clock genes in the skeletal muscle in both mice (Wolff and Esser 2012; Yasumoto et al. 2015) and humans (Zambon et al. 2003). Therefore, whether the increased NAMPT protein content in human skeletal muscle after aerobic and resistance training is a consequence of transcriptional activity of the clock machinery or another posttranscriptional mechanism warrants further investigation. ...
Collectively, exercise training reverses the age‐dependent decline in skeletal muscle NAMPT abundance, and our findings highlight the value of exercise training in ameliorating age‐associated deterioration of skeletal muscle function.
