The NAD+/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling
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NAD(+) is an important cofactor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylases. We show that NAD(+) levels are reduced in aged mice and Caenorhabditis elegans and that decreasing NAD(+) levels results in a further reduction in worm lifespan. Conversely, genetic or pharmacological restoration of NAD(+) prevents age-associated metabolic decline and promotes longevity in worms. These effects are dependent upon the protein deacetylase sir-2.1 and involve the induction of mitonuclear protein imbalance as well as activation of stress signaling via the mitochondrial unfolded protein response (UPR(mt)) and the nuclear translocation and activation of FOXO transcription factor DAF-16. Our data suggest that augmenting mitochondrial stress signaling through the modulation of NAD(+) levels may be a target to improve mitochondrial function and prevent or treat age-associated decline.
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A disturbed balance between nuclear DNA-encoded and mtDNA-encoded OXPHOS proteins, independent of mitochondrial content, has previously been associated with activation of mitochondrial quality control mechanisms such as the mtUPR.
“A disturbed balance between the nuclear DNA-encoded and mitochondrial DNA (mtDNA)-encoded OXPHOS proteins, independent of mitochondrial content, has previously been associated with the activation of mitochondrial quality control mechanisms such as the mtUPR [32, 33].”
From Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity (2021) · cites this paper as [33]
The Results (‘Early phase activation of UPRmt by NAD+ boosters’; page unavailable) associate a changed ratio of nuclear- and mtDNA-encoded OXPHOS proteins with UPRmt activation. The cited passages do not establish that this association is independent of mitochondrial content; the mammalian-cell Results also report mitochondrial biogenesis after treatment. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn brain tissues from old normal mice and accelerated aging mice, declining NAD+ contributes to age-associated decline in mitochondrial biogenesis via impaired SIRT1-PGC-1a signaling.
“In brain tissues from old normal mice and accelerated aging mice, a decline in NAD+ levels contributes to the age-associated decline of mitochondrial biogenesis via impaired SIRT1-PGC-1a signaling (Fang et al., 2014; Mouchiroud et al., 2013; Stein and Imai, 2014).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Mouchiroud et al., 2013
NAD+ is central to mitochondrial homeostasis, including mitochondrial biogenesis, mitophagy, UPRmt, and nuclear-mitochondrial communication.
“NAD+ is central to mitochondrial homeostasis, including in mitochondrial biogenesis, mitophagy, the mitochondrial unfolded protein response (UPRmt), and nuclear-mitochondrial communication (Fang et al., 2014; Gomes et al., 2013; Mouchiroud et al., 2013).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Mouchiroud et al., 2013
Reduced NAD+ downregulates SIRT1, an NAD+-dependent deacetylase involved in mitochondrial homeostasis and XPA repair activity.
“They observed that the reduced level of NAD+ downregulated SIRT1, a NAD+- dependent deacetylase involved in regulating mitochondrial homeostasis and XPA repair activity 91–93.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [92]
A supraphysiologic dose of NAM (1-5 mM compared with 200 μM used in lifespan extension experiments) has been associated with reduced lifespan in yeast and C. elegans.
“a supraphysiologic dose of NAM (1–5 mM as compared with 200 μM used in experiments with lifespan extension190) has also been associated with reduced lifespan in yeast and C. elegans190–192.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [190]
In wild-type yeast and C. elegans, low micromolar concentrations of NR extend lifespan in a sirtuin-dependent manner.
“In both wild-type yeast and C. elegans, low (micromolar) concentrations of NR extend lifespan in a sirtuin-dependent manner135,189,190.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [190]
Administration of NAM extends lifespan in wild-type C. elegans.
“lifespan extension was observed on administration of NAM to wild-type C. elegans190.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [190]
In C. elegans, PARP inhibition results in significant lifespan extension in wild-type worms, in a model of ataxia telangiectasia and under hyperglycaemic conditions.
“In C. elegans, PARP inhibition results in a significant lifespan extension in wild-type worms190, in a model of ataxia telangiectasia135 and under hyperglycaemic conditions221.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [190]
Both NR and NMN increase the lifespan of worms.
“both NR and NMN increase the lifespan of worms [201]”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [201]
NAD+ supplementation in C. elegans extends worm lifespan via induction of the mitochondrial unfolded protein response and upregulation of mitochondrial superoxide dismutase.
“Supplementation of NAD+ levels in C elegans ((Mouchiroud et al. 2013)) extends worm lifespan via the induction of the mitochondrial unfolded protein response and upregulation of mitochondrial superoxide dismutase.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Mouchiroud et al. 2013
Pharmacological PARP1 inhibition in nematodes boosts mitochondrial biogenesis and prolongs lifespan.
“In nematodes, pharmacological inhibition of PARP1 increases mitochondrial biogenesis and extends lifespan84.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [84]
PARP inhibitors lessen genetic mitochondrial metabolism defects in C. elegans.
“Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans.”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Mouchiroud et al., 2013
MRL-45696 effectively inhibited PARP activity and OCR in mev-1 mutants.
“MRL-45696 effectively inhibited PARP activity (Figure 4C) and OCR in mev-1 mutants (Figure 4D), as previously noticed in wild-type worms using other Paribs (Mouchiroud et al., 2013).”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Mouchiroud et al., 2013
C2C12 cell results suggest SIRT1 is needed for Parib-induced mitonuclear imbalance and UPRmt.
“While it is not clear how Paribs trigger mitonuclear imbalance and UPRmt in mammalian cells, results obtained in C2C12 cells suggest that SIRT1 is required for such an effect (Figure S4C), consistent with the mechanisms reported in worms (Mouchiroud et al., 2013).”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Mouchiroud et al., 2013
Paribs raise mitochondrial respiratory capacity in worms by triggering UPRmt in a SIRT1-dependent way.
“Paribs increase mitochondrial respiratory capacity in worms by triggering the mitochondrial unfolded protein response (UPRmt-) in a SIRT1-dependent manner (Mouchiroud et al., 2013).”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Mouchiroud et al., 2013
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- Authors
- Mouchiroud, L., Houtkooper, R. H., Moullan, N., Katsyuba, E., Ryu, D., Cantó, C., Mottis, A., Jo, Y.-S., Viswanathan, M., Schoonjans, K., Guarente, L., & Auwerx, J.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- Amsterdam UMC Location University of Amsterdam (NL)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Auwerx, Johan
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 154
- Issue
- 2
- Pages
- 430-441
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3753670
- OpenAlex
- W2012043504
- Cited by
- 1,210
- References
- 58
- Citations by year
- 2026: 60 · 2025: 90 · 2024: 102 · 2023: 90 · 2022: 116 · 2021: 117 · 2020: 124 · 2019: 103 · 2018: 88 · 2017: 84 · 2016: 91 · 2015: 63 · 2014: 67 · 2013: 12
- FWCI
- 36.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (125487, 124713)
- ZonMw (91613050)
- National Institute on Aging (R56AG015339, R01AG043930, R01AG015339)
- National Heart, Lung, and Blood Institute (R01HL106511)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- NAD+, sirtuins, sir-2.1, longevity, aging, mitochondrial unfolded protein response, FOXO, DAF-16, Caenorhabditis elegans
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Aging, Animals, Longevity, Mitochondria, NAD, Transcription Factors, Signal Transduction, Caenorhabditis elegans, Reactive Oxygen Species, Hepatocytes, Caenorhabditis elegans Proteins, Sirtuins, Mice, Forkhead Transcription Factors, Sirtuin 1, Unfolded Protein Response
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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