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Cited by 384Sirtuins and Resveratrol in MedicineBiochemical and Molecular ResearchGenetics, Aging, and Longevity in Model Organisms

A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline

Open access
Tarragó, Mariana G., Chini, Claudia C.S., Kanamori, Karina S., Warner, Gina M., Caride, Ariel, de Oliveira, Guilherme C., Rud, Micaela, Samani, Adrienne +11 more·2018·Cell Metabolism
DOI 10.1016/j.cmet.2018.03.016PMC PMC5935140
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Abstract

SUMMARY Aging is characterized by the development of metabolic dysfunction and frailty. Recent studies show that a reduction in nicotinamide adenine dinucleotide (NAD+) is a key factor for the development of age-associated metabolic decline. We recently demonstrated that the NADase CD38 has a central role in age-related NAD+ decline. Here we show that a highly potent and specific thiazoloquin(az)olin(on)e CD38 inhibitor, 78c, reverses age-related NAD+ decline and improves several physiological and metabolic parameters of aging, including glucose tolerance, muscle function, exercise capacity, and cardiac function in mouse models of natural and accelerated aging. The physiological effects of 78c depend on tissue NAD+ levels, and were reversed by inhibition of NAD+ synthesis. 78c increased NAD+ levels, resulting in activation of pro-longevity and health span-related factors including sirtuins, AMPK, and PARPs. Furthermore, in animals treated with 78c we observed inhibition of pathways that negatively affect health span, such as mTOR-S6K and ERK, and attenuation of telomere-associated DNA damage, a marker of cellular aging. Together, our results detail a novel pharmacological strategy for prevention and/or reversal of age-related NAD+ decline and subsequent metabolic dysfunction.

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Crossref · 10.1016/j.cmet.2018.03.016

Cites

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Claims the paper makes

0 of 50 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    78c is tenfold less potent against rhCD38 cyclase activity than against its hydrolase activity (Ki 100 ± 28 nM vs. 9.7 ± 1.5 nM).

    “78c was 10-fold less potent against the cyclase activity than the hydrolase activity of rhCD38 (Ki 100 ± 28 nM vs. 9.7 ± 1.5 nM, respectively)”
    Quote in the paperSubstantial claim
  • Findingown data

    78c does not inhibit the Aplysia californica ADP-ribosyl cyclase at concentrations up to 50 nM.

    “The Aplysia enzyme was not inhibited by 78c at concentrations up to 50 nM”
    Quote in the paperSubstantial claim
  • Findingown data

    NMN lowers the apparent Ki for 78c in a hyperbolic manner.

    “NMN decreased the apparent Ki for 78c in a hyperbolic manner”
    Quote in the paperNot a substantial claim
  • Findingown data

    78c does not affect CD157 catalytic activity with NAD+ or NR as substrate.

    “observed no effect of 78c in the CD157 catalytic activities”
    Quote in the paperSubstantial claim
  • Findingown data

    78c inhibition of CD38 NADase activity is reversible.

    “The inhibitory effect of 78c on CD38 NADase activity was reversible”
    Quote in the paperNot a substantial claim
  • May combine two claims. 60
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingown data

    78c inhibits human and murine CD38 potently, with a Ki in the low nanomolar range.

    “78c is a potent inhibitor of both human CD38 (recombinant, rhCD38) and murine CD38, with a Ki in the low nanomolar range”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c inhibits CD38 uncompetitively, lowering both apparent Vmax and Km for NAD+.

    “uncompetitive (Fig. 1B–C) decreasing both apparent Vmax and Km of CD38 for NAD+”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ADPR and cADPR do not significantly affect these kinetic parameters.

    “neither ADPR nor cADPR had significant effects on these kinetic parameters”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    NAM lowers the apparent V0 and raises the Ki for 78c.

    “NAM decreased the apparent V0 and increased the Ki for 78c”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Olaparib raises cellular NAD+, and combining it with 78c produces an additive increase.

    “The PARP inhibitor olaparib increased cellular NAD+ levels by itself, and combination of olaparib with 78c produced an additive effect on the increase in cellular NAD+”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c causes a small but significant increase in VO2 and TEE in P44+/+ mice, with no other calorimetric changes.

    “except for a small, but significant increase in oxygen consumption (VO2) and total energy expenditure (TEE), it did not cause other alterations in calorimetric parameters”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    78c increases exercise capacity in a downhill running protocol to exhaustion.

    “78c also increased exercise capacity when mice were exercised to exhaustion in this protocol”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Olaparib's NAD+-boosting effect persists in liver and spleen of CD38 KO mice and appears stronger in skeletal muscle.

    “the NAD+-boosting effects of olaparib were not only preserved in tissues of CD38 KO mice such as liver and spleen, but appeared to be even potentiated in skeletal muscle”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    78c improves glucose homeostasis in 2-year-old mice without changing body weight.

    “after treatment with 78c, we noted an improvement in glucose homeostasis parameters in 2-year-old mice without changes in body weight”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c improves spontaneous physical activity and activity-related energy expenditure in 2-year-old mice.

    “both spontaneous physical activity and activity-related energy expenditure (AEE) were statistically significantly improved in 2-year-old mice treated with 78c”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c does not significantly change muscle weight, fiber subtype distribution, or Pax7+ satellite cell number.

    “No significant changes were observed in muscle weight, fiber subtype distribution, or number of Pax7+ muscle satellite cells”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    78c has no significant effect on NAD+ or exercise tolerance in young (3-month-old) mice.

    “it had no significant effect on either NAD+ levels or exercise tolerance in young (3-month-old) mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c raises NAD+ in several tissues and improves glucose tolerance in P44+/+ mice.

    “Treatment of the P44+/+ mice with 78c increased NAD+ levels in several tissues and improved glucose tolerance”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    P44+/+ mice have higher CD38 NADase activity and CD38 expression than age-matched controls.

    “CD38 NADase activity and CD38 expression were higher than age-matched controls”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aged control muscle shows large fibrotic streaks with WGA staining, while 78c-treated muscle shows nearly none.

    “histological sections of muscle from aged control mice stained with the fibrosis marker wheat germ agglutinin (WGA) showed large fibrotic streaks, while samples from 78c–treated mice had nearly no signs of fibrosis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c nearly doubles NAD+ in WT MEFs but does not change NAD+ in CD38 KO MEFs.

    “78c nearly doubled the amount of NAD+ in WT MEFs, but had no effect on cellular NAD+ levels in CD38 KO MEFs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aging in mice changes muscle architecture: myofiber size, centrally located nuclei, CD45+ inflammatory infiltration, and necrotic myofibers increase.

    “several changes in muscle architecture including: 1) changes in myofiber size; 2) an increase in centrally located nuclei; 3) infiltration of CD45+ inflammatory cells; and 4) an increase in abundance of necrotic myofibers”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two-year-old mice have lower tissue NAD+ and worse glucose tolerance than younger mice.

    “aged mice (2-year-old) had lower tissue NAD+ levels, and worse glucose tolerance compared to younger mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aging in mice decreases exercise capacity and spontaneous physical activity.

    “There was an age-dependent decrease in exercise capacity, spontaneous physical activity”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c decreases centrally located nuclei, inflammatory infiltrates, and necrotic myofibers by more than 70% in aged mice.

    “the number of centrally located nuclei, presence of inflammatory cell infiltrates, and number of necrotic myofibers decreased by more than 70%”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c increases ATP and ATP/O2 coupling in skeletal muscle.

    “78c treatment increased not only NAD+ levels and exercise tolerance, but also ATP and ATP/O2 coupling in skeletal muscle”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c does not directly inhibit or stimulate SIRT1 or NAMPT.

    “we saw that 78c does not directly inhibit or stimulate these enzymes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c has no detectable effect on PARP1 activity in vitro, whereas olaparib fully inhibits it.

    “While the PARP inhibitor olaparib completely inhibited the activity of this enzyme, 78c had no detectable effects on PARP1 activity”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aged control mice show lower ejection fraction and fractional shortening, and higher left ventricle systolic volume and isovolumetric contraction time than young controls.

    “Aged control mice showed a decline in ejection fraction (EF) and fractional shortening (FS), and an increase in left ventricle volume during systole (LVVs) and isovolumetric contraction time (IVCT) parameters related to cardiac straining when compared with young control mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CD38-CI mice express CD38 at WT-like levels but have no detectable CD38 NADase activity.

    “Although the CD38-CI animals expressed levels of CD38 similar to the WT mice (see Western blot in Fig. 1F and Fig. S1N), they had no detectable CD38 NADase activity”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c does not change food intake or weight in P44+/+ mice.

    “without changes in food intake or weight of these mice”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    78c significantly increases maximal running speed in 1-year-old mice but not in 2-year-old mice.

    “There was an increase in maximal running speed that was statistically significant in 1-year-old mice but did not reach statistical significance in 2-year-old mice”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    78c treatment for 10 weeks significantly raises NAD+, NMN, and NR in liver, skeletal muscle, and spleen, except liver NR which is not significant.

    “Liver, skeletal muscle, and spleen of mice treated with 78c for 10 weeks showed a statistically significant increase in the levels of all three NAD+ metabolites, with the exception of NR levels in the liver, which had an increase that did not reach statistical significance”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Expressing CD38 in 293T cells increased acetylation of p65 and pan-cellular acetylation.

    “expression of CD38 in 293T cells increased acetylation of p65, a substrate of sirtuins 1, 2, and 6, and also pan-cellular acetylation (Fig. S5A–B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    With CD38+ cells in the upper chamber, NMN does not raise NAD+ in AML12 cells, but 78c reverses this effect.

    “When CD38+ cells were present in the upper chamber, treatment with NMN did not promote an increase in NAD+ levels in the AML12 cells. However, treatment with 78c reversed the effect of the CD38+ cells on the NAD+-boosting effect of NMN in the AML12 cells”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 293T cells with p53-mediated PARylation induction, CD38 co-expression decreased PARylation, and 78c reversed this decrease.

    “In 293T cells, with p53-mediated induction of PARylation, co-expression of CD38 caused a decrease in PARylation, and this effect was reversed by 78c (Fig. S5E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In AML12 cells treated with rhCD38, adding 78c together with NMN reversed the rhCD38 effect and increased cellular NAD+ levels.

    “Addition of 78c and NMN together to the media of AML12 cells treated with rhCD38 reversed this effect, leading to an increase in cellular NAD+ levels (Fig. 4I).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    78c reversed the effect of CD38 expression and promoted deacetylation of lysines in p65 and other proteins.

    “78c reversed the effect of CD38 expression and promoted the deacetylation of lysines in p65 and other proteins (Fig. S5A–B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Liver CD38 staining occurs in CD45+ cells (Kupffer and immune cells) and CD45− sinusoidal cells (endothelial and stellate cells).

    “CD38 staining in the liver was observed in both CD45+ cells (e.g. resident macrophages-Kupffer cells and other infiltrating/resident immune cells), and CD45− cells located in the sinusoidal region (e.g. endothelial cells, and stellate cells)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In AML12 cells exposed to NMN plus rhCD38, pan-protein acetylation rose and the AMPK pathway was inhibited.

    “Treatment of AML12 cells with NMN in the presence of rhCD38 led to an increase in pan-protein acetylation and inhibition of the AMPK pathway (Fig. S4H).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In skeletal muscle, most CD38+ cells are endothelial (CD31+), with abundant CD38+ immune cells (CD45+) and putative FAPs/fibroblasts (CD31−/CD45−/Sca1+).

    “In skeletal muscle the majority of CD38+ cells are endothelial (CD31+); however, CD38+ immune cells (CD45+) and putative fibro-adipogenic precursors (FAPs) and fibroblasts (CD31−/CD45−/Sca1+) are also abundant”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Liver sections show no CD38 staining in hepatocytes but abundant CD38+ cells.

    “immunofluorescent staining of mouse liver sections with an anti-CD38 antibody showed that hepatocytes did not stain for CD38, CD38+ cells were abundant in this tissue”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    After 78c dosing, measured 78c concentrations were plasma 0.007 μg/mL; brain 0.000 μg/g; heart 0.003 μg/g; kidney 0.005 μg/g; liver 0.024 μg/g; pancreas 0.002 μg/g; and spleen 0.0048 μg/g.

    “The results of the measurements were: plasma (0.007 μg/mL); brain (0.000 μg/g); heart (0.003 μg/g); kidney (0.005 μg/g); liver (0.024 μg/g); pancreas (0.002 μg/g) and, spleen (0.0048 μg/g).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    78c was detectable in cellular extracts of cultured cells treated with different concentrations of 78c.

    “We also observed that 78c could be detected in cellular extracts of cultured cells treated with different concentration of 78c.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    This age-related NAD+ decline causes mitochondrial dysfunction and metabolic abnormalities.

    “causing mitochondrial dysfunction and metabolic abnormalities”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Braidy et al., 2011 source

      Not checked in the free run.

    • cites Camacho-Pereira et al., 2016 source

      Not checked in the free run.

    • cites Gomes et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    78c is a specific, reversible, uncompetitive CD38 inhibitor that preferentially inhibits CD38 NADase activity.

    “Collectively, these studies establish that 78c is a specific, reversible, and uncompetitive CD38i that preferentially inhibits CD38 NADase activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PARP1 is the main PARP enzyme in mammalian tissues and consumes NAD+ during catalysis.

    “PARP1 is the main PARP enzyme in mammalian tissues and utilize NAD+ during its catalysis”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bai et al., 2011 source

      Not checked in the free run.

    • cites Bai and Cantó, 2012 source

      Not checked in the free run.

    • cites Imai and Guarente, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    78c raises tissue NAD+ and ameliorates age-related glucose intolerance in natural aging and a progeroid mouse model.

    “we conclude that the CD38i 78c promotes an increase in tissue NAD+ levels and ameliorates age-related glucose intolerance in both natural aging and in a progeroid mouse model.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    78c raises tissue NAD+ by inhibiting CD38 NADase activity, not by affecting other NAD+ metabolizing enzymes.

    “these data clearly demonstrate that 78c increases tissue NAD+ levels by a mechanism dependent on the inhibition of the NADase catalytic activity of CD38, and not via its effect on other NAD+ metabolizing enzymes.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Aging increases glucose intolerance, insulin resistance, and diabetes, decreases physical activity and exercise capacity, and impairs skeletal muscle architecture and cardiac function.

    “aging leads to an increased incidence of glucose intolerance, insulin resistance, and diabetes, as well as a decrease in physical activity and exercise capacity, and impairment in skeletal muscle architecture and cardiac function”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Huffman et al., 2016 source

      Not checked in the free run.

    • cites Justice et al., 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Inhibiting PARP1 can raise cellular NAD+ by reducing its degradation.

    “several studies have proposed that PARP1 inhibition can be used to promote increases in cellular levels of NAD+ by decreasing its degradation”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bai et al., 2011 source

      Not checked in the free run.

    • cites Bai and Cantó, 2012 source

      Not checked in the free run.

    • cites Imai and Guarente, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    78c does not directly affect PARP activity, and its NAD+-boosting effect is independent of PARP activity.

    “These data together demonstrate that 78c does not directly influence the activity of PARP, and that its NAD+-boosting effects are mediated by a mechanism that is independent of PARP activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    78c is a potent and specific CD38 inhibitor.

    “Thus, our studies establish 78c as a potent and specific CD38i.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    78c improves glucose homeostasis, exercise capacity, muscle architecture, and cardiac function in aged mice.

    “Our data together show that 78c can promote significant improvement in several physiological parameters including: glucose homeostasis, exercise capacity, muscle architecture and cardiac function in aged mice.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Sirtuins have been linked to regulation of chromosomal integrity, DNA damage repair, metabolism, aging, health span, and longevity.

    “have been implicated in the regulation of chromosomal integrity, DNA damage repair, metabolism, aging, health span, and longevity”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cantó and Auwerx, 2012

      Not checked in the free run.

    • cites Escande et al., 2013 source

      Not checked in the free run.

    • cites Imai and Guarente, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    78c may activate not only SIRT1 but also other NAD+-dependent sirtuins linked to health span and longevity.

    “this mechanism of action suggests that 78c may activate not only SIRT1, but also other NAD+-dependent health span and longevity-associated sirtuins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    78c may prevent or reverse accumulation of cellular senescence in tissues.

    “Since TAF have been associated with cellular senescence in vivo, our data indicate that 78c may either prevent or reverse the accumulation of cellular senescence in tissues.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Telomere-associated foci are associated with cellular senescence in vivo.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    CD38 staining specificity was confirmed by negative controls.

    “The specificity of CD38 staining was confirmed in negative control experiments”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Increasing tissue NAD+ levels with NAD+ precursors such as NMN and NR improves health span, mitigates age- and metabolic disease-associated decline, and may increase longevity.

    “Recently, several reports have demonstrated that increasing NAD+ levels in tissues, through the use of NAD+ precursors such as NMN and NR, improves health span, mitigates age and metabolic disease-associated decline, and may increase longevity”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cantó and Auwerx, 2012

      Not checked in the free run.

    • cites Li et al., 2017

      Not checked in the free run.

    • cites Mills et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    78c raises tissue NAD+ levels, which likely stimulates pan-activation of NAD+-dependent enzymes including several sirtuins and PARPs.

    “Our results combined indicate that 78c promotes an increase in tissue NAD+ levels which likely stimulates pan-activation of NAD+-dependent enzymes including several sirtuins and PARPs.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The AMPK pathway is pro-longevity, while the mTOR-p70S6K and ERK pathways negatively correlate with health span.

    “We further explored the effect of 78c on pro-longevity pathways, such as the AMPK pathway, and in pathways that negatively correlate with health span, such as the mTOR-p70S6K and ERK pathways (Huffman et al., 2016; Justice et al., 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Huffman et al., 2016 source

      Not checked in the free run.

    • cites Justice et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    78c activates pro-longevity pathways such as AMPK and inhibits pathways negatively correlated with longevity such as p70S6K and ERK.

    “Furthermore, 78c promotes activation of pro-longevity pathways, such as AMPK, and inhibition of pathways negatively correlated with longevity, such as p70S6K and ERK.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    78c-mediated inhibition of CD38 leads to an NAD+ boost that increases activity of several NAD+-dependent enzymes, including PARPs and sirtuins.

    “Our combined data suggest that 78c-mediated inhibition of CD38 leads to an NAD+ boosting effect that promotes increase in activity of several NAD+-dependent enzymes including PARPs and sirtuins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The 78c-induced rise in tissue NAD+ leads to activation of multiple NAD+-dependent sirtuins, including SIRT1, SIRT3, SIRT6, SIRT5, and SIRT7.

    “These data further support the concept that 78c-induced increase in tissue NAD+, leads to activation of multiple NAD+-dependent sirtuins such as the deacetylases (SIRT1, SIRT3, and SIRT6), and the demalonylases and desuccinylases, namely SIRT5 and 7.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Telomere regions are difficult to repair because non-homologous recombination is inhibited, leading to a persistent DNA damage response that accumulates with aging.

    “In contrast to the rest of the genome, telomere regions cannot be easily repaired due to inhibition of non-homologous recombination, resulting in a persistent DNA damage response which accumulates during aging.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jurk et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    78c may increase the cellular availability of NAD+ to sirtuins by inhibiting CD38/NADase activity, thereby promoting NAD+-dependent lysine deacetylation of proteins.

    “These results suggest that 78c may increase the cellular availability of NAD+ to sirtuins via inhibition of CD38/NADase activity, thereby promoting NAD+-dependent lysine deacetylation of proteins.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Sirtuins are enzymes that remove covalent modifications such as acetylation, malonylation, and succinylation from lysine residues in proteins.

    “Sirtuins are enzymes that remove specific covalent modification in lysine residues, such as acetylation, malonylation, and succinylation, in several proteins”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cantó and Auwerx, 2012

      Not checked in the free run.

    • cites Escande et al., 2013 source

      Not checked in the free run.

    • cites Imai and Guarente, 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PARP1 activity positively correlates with longevity across species.

    “It has been observed that PARP1 activity positively correlates with longevity in different species (Bakondi et al., 2011; Beneke et al., 2010; Noren-Hooten et al., 2012)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bakondi et al., 2011 source

      Not checked in the free run.

    • cites Beneke et al., 2010 source

      Not checked in the free run.

    • cites Noren-Hooten et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PARP activity declines during aging, and NAD+-boosting with NMN can restore PARP1 activity and promote health span.

    “data from a recent study demonstrate that PARP activity decreases during the aging process and that NAD+-boosting with NMN can restore PARP1 activity and promote health span (Li et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Li et al., 2017

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CD38 inhibition in humans has recently been targeted using biologicals such as CD38-specific blocking antibodies.

    “CD38 inhibition in humans has been recently targeted using biologicals such as CD38-specific blocking antibodies (Shallis et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shallis et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Echocardiography images were analyzed in a blinded fashion.

    “Images were analyzed in a blinded fashion as previously described and validated (Hill et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hill et al., 2000 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study did not examine lifespan and longevity in naturally aged animals.

    “we did not study lifespan and longevity in natural aged animals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    78c has a unique mechanism of action for the compound and for the role of CD38 in organismal NAD+ homeostasis.

    “This indicates a unique mechanism of action for this compound and for the role of CD38 in organismal NAD+ homeostasis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In this study, 78c was administered intraperitoneally rather than orally.

    “in this study, the route of administration of 78c was intraperitoneally and the ideal therapeutic route would be orally.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because CD38 is mostly an ecto-enzyme, one effect of 78c is to inhibit degradation of extracellular NAD+ and its precursors, improving global organismal NAD+ homeostasis.

    “because CD38 is mostly an ecto-enzyme, it appears that one of the effects of 78c is to inhibit the degradation of extracellular NAD+ and its precursors improving global organismal NAD+ homeostasis.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: CD38 is mostly an ecto-enzyme.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The specific mechanisms linking 78c-induced NAD+ increases to physiological and metabolic functions were not fully delineated in the studies.

    “The specific mechanisms connecting the increases in NAD+ levels induced by 78c with physiological and metabolic functions were not fully delineated in our studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several CD38-specific antibodies are being studied or have been approved by the FDA for treating human cancers.

    “several of these antibodies are either being studied or have been approved by the FDA for the treatment of human cancers (Shallis et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shallis et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All animal protocols were approved by the Mayo Clinic IACUC, and the studies followed the NIH Guide for the Care and Use of Laboratory Animals.

    “All protocols requiring animal manipulation were approved by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC), and studies were conducted in adherence to the NIH Guide for the Care and Use of Laboratory Animals.”
    Quote in the paperNot a substantial claim
73 of 73

  • The paper relies on this without support.

    The mechanisms, specificity, and biological effects of 78c on age-related NAD+ decline and metabolic dysfunction had not been investigated before this study.

    “However, their mechanisms of action, specificity, and biological effects on age-related NAD+ decline and metabolic dysfunction have not been investigated.”

  • The paper relies on this without support.

    Findings in mouse models of aging can be translated to a viable pharmacological strategy for age-related metabolic dysfunction in humans.

    “In summary, these studies establish CD38 as a viable target for pharmacological NAD+-replacement therapy for age-related metabolic dysfunction.”

  • The paper relies on this without support.

    NAD+ decline has a causal role in age-related metabolic dysfunction and in the development of age-related diseases.

    “Since NAD+ decline appears to have a causal role in age-related metabolic dysfunction and the development of age-related diseases”

  • The paper relies on this without support.

    CD38 is mostly an ecto-enzyme.

    “because CD38 is mostly an ecto-enzyme”

  • The paper relies on this without support.

    Telomere-associated foci are associated with cellular senescence in vivo.

    “Since TAF have been associated with cellular senescence in vivo”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mouse models including Parp1-knockout and Cd38-knockout mice, or mice treated with PARP or CD38 inhibitors, have supraphysiological levels of NAD+, are protected from obesity, have increased metabolic rates, and have relatively normal glucose metabolism during high-fat diet conditions and during ageing.

    “In further support of this model, numerous studies have now shown that mouse models including Parp1-knockout and Cd38-knockout mice, or mice treated with PARP or CD38 inhibitors, have supraphysiological levels of NAD+. They are also protected from obesity, have increased metabolic rates and have (relatively) normal glucose metabolism during high-fat diet conditions and during ageing42,89–91.”

    From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [91]

  • CD38 levels increase in mammalian tissues with age, and CD38 has been proposed to be the major NAD+-consuming enzyme responsible for the decline in NAD+ levels during ageing.

    “Recently, it was shown that CD38 levels increase in mammalian tissues with age, and CD38 has been proposed to be the major NAD+-consuming enzyme responsible for the decline in NAD+ levels during ageing42,91.”

    From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [91]

  • Treating aged mice with compound 78c lessens metabolic dysfunction.

    “78c also prevents age-related declines in NAD+ levels in mice, and treatment of aged mice with this compound was shown to ameliorate metabolic dysfunction, reduce DNA damage accumulation and improve muscle function91,231.”

    From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [91]

  • Treating aged mice with compound 78c improves muscle function.

    “78c also prevents age-related declines in NAD+ levels in mice, and treatment of aged mice with this compound was shown to ameliorate metabolic dysfunction, reduce DNA damage accumulation and improve muscle function91,231.”

    From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [91]

  • Treating aged mice with compound 78c reduces DNA damage accumulation.

    “78c also prevents age-related declines in NAD+ levels in mice, and treatment of aged mice with this compound was shown to ameliorate metabolic dysfunction, reduce DNA damage accumulation and improve muscle function91,231.”

    From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [91]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • BubR1 mouse-model citation has conflicting years

    Minor

    The survival result cites Baker et al. as a 2004 publication, but the paper's reference list gives 2014 for that Baker publication.

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. Rechsteiner, 1978, Turnover of nicotinamide adenine dinucleotide in cultures of human cells, J. Cell. Physiol., 88, 207, 10.1002/jcp.1040880210 · DOI

Cited by

Sorted by citations

Authors
Tarragó, M. G., Chini, C. C. S., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., Rud, M., Samani, A., Hein, K. Z., Huang, R., Jurk, D., Cho, D. S., Boslett, J. J., Miller, J. D., Zweier, J. L., Passos, J. F., Doles, J. D., Becherer, D. J., & Chini, E. N.
Affiliations
  • Mayo Clinic (US)
  • Newcastle University (GB)
  • The Ohio State University (US)
  • Viamet Pharmaceuticals (United States) (US)
Corresponding author
Chini, Eduardo N.
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2018-05
Volume
27
Issue
5
Pages
1081-1095.e10
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2018.03.016
PMC
PMC5935140
OpenAlex
W2800027563
Semantic Scholar
6071bd620228dd7f4bb54ebb2b9c4bb9f9d3a28a
Cited by
384
References
60
Citations by year
2026: 44 · 2025: 60 · 2024: 55 · 2023: 47 · 2022: 52 · 2021: 50 · 2020: 38 · 2019: 33 · 2018: 5
FWCI
17.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Ted Nash Long Life Foundation
  • the Glenn Foundation for Medical Research
  • Calico Laboratories
  • Mayo Foundation
  • NIH (AG-26094, CA102701-08, P30DK084567, AR-66696)
  • BBSRC (BB/K017314/1)
  • MRC Arthritis UK
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
CD38, aging, metabolic dysfunction, glucose tolerance, muscle function, exercise capacity, cardiac function, sirtuins, AMPK, poly(ADP-ribose) polymerase, ERK, healthspan, accelerated aging
MeSH terms
Physical Functional Performance, AMP-Activated Protein Kinase Kinases, Aging, Animals, DNA Damage, Enzyme Inhibitors, Humans, NAD, Poly(ADP-ribose) Polymerases, Protein Kinases, Quinolines, Triazoles, Cellular Senescence, Glucose Intolerance, MAP Kinase Signaling System, Sirtuins, Mice, ADP-ribosyl Cyclase 1, TOR Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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