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Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging
Open accessAbstract
Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.
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In the citing paper
“Notably, NAD+ declines with age in several tissues”
From Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype (2016) · cites this paper as Gomes et al., 2013
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Although HIF1α has been shown to increase during aging affecting nuclear–mitochondrial communication”
From Mfn2 deficiency links age‐related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway (2016) · cites this paper as Gomes et al, 2013
In the citing paper
“Metformin’s direct activation of SIRT1 may help combat age-related mitochondrial dysfunction which is attributed to a reduction in SIRT1 activity leading to downregulation of a nuclear-encoded mitochondrial transcription factor A (TFAM) and declines in NAD+ levels”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Gomes et al. 2013
In the citing paper
“NAD+ is a vital redox cofactor for metabolism and ATP production, and a key substrate for at least four families of enzymes involved in healthspan and longevity (Fang et al., 2017; Gomes et al., 2013; Verdin, 2015).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Gomes et al., 2013
In the citing paper
“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 Gomes et al., 2013
In the citing paper
“Furthermore, NAD+ depletion induces a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication, which contributes to the decline in mitochondrial function with age (Gomes et al., 2013).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Gomes et al., 2013
In the citing paper
“NMN enhances mitochondrial function in various organs, including skeletal muscle201, kidney202–204, liver203, heart205, eyes206, brain161 and the cardiovascular system207, and can mitigate oxidative stress in the vasculature208, including improvements in neurovascular coupling responses in the aged cortex of the brain209.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [201]
In the citing paper
“These studies also documented that NMN has a significant effect on improving disease conditions and reducing age-related physiological decline [203–206].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [204]
In the citing paper
“causing mitochondrial dysfunction and metabolic abnormalities”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Gomes et al., 2013
In the citing paper
“Recent studies show that levels of NAD+ and its precursors decline during chronological aging and in progeroid syndromes”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Gomes et al., 2013
In the citing paper
“many of these phenotypes are regulated by NAD+ availability and the activity of NAD+-dependent enzymes”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Gomes et al., 2013
In the citing paper
“These data indicate that age-related mitochondrial dysfunction is reversible and contributes to dysfunction in aged tissues.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [118]
In the citing paper
“A recent study reported that reduced levels of NAD+ contribute to the mitochondrial decay associated with skeletal muscle aging and that SIRT1 modulates this process118.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [118]
In the citing paper
“The imbalance between nuclearly and mitochondrially encoded respiratory chain subunits caused by declining nuclear NAD+ was shown to disrupt oxidative phosphorylation in aged mice, whereas raising nuclear NAD+ levels restored mitochondrial function in old mice.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [118]
In the citing paper
“The imbalance between nuclearly and mitochondrially encoded respiratory chain subunits caused by declining nuclear NAD+ was shown to disrupt oxidative phosphorylation in aged mice, whereas raising nuclear NAD+ levels restored mitochondrial function in old mice.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [118]
In the citing paper
“A recent study reported that reduced levels of NAD+ contribute to the mitochondrial decay associated with skeletal muscle aging and that SIRT1 modulates this process118.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [118]
In the citing paper
“In aged mice, loss of SIRT1 activity (via a decline in NAD+ levels) leads to increased activity of the HIF-1α transcription factor that is linked with age-associated mitochondrial dysfunction and changes in oxidative phosphorylation (Gomes et al., 2013).”
From The Aging Epigenome (2016) · cites this paper as Gomes et al., 2013
In the citing paper
“nuclear-mitochondrial communication is also a key determinant of longevity in animals (Chang et al., 2015; Gomes et al., 2013).”
From The Aging Epigenome (2016) · cites this paper as Gomes et al., 2013
In the citing paper
“Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1–3”
From Trigonelline Is an NAD+ Precursor That Improves Muscle Function during Ageing and Is Reduced in Human Sarcopenia (2024) · cites this paper as [1]
In the citing paper
“In rodents, the age-dependent decline in NAD+ levels decreases SIRT1 activity, ultimately affecting mitochondrial homeostasis48.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [48]
In the citing paper
“In 22-month-old mice, NMN restored NAD+ levels and markers of mitochondrial decline during ageing48, while reducing age-associated body weight gain and increasing energy metabolism and physical activity254.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [48]
In the citing paper
“Reduced NAD+ levels in skeletal muscle of aged or Nampt deficient mice alter mitochondrial bioenergetics and impair muscle mass, strength and endurance49,50,52,53”
From Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities (2019) · cites this paper as [50]
In the citing paper
“However, low NAD+ is a causal mechanism for mitochondrial perturbations in age-related pathologies in model organisms49–51.”
From Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities (2019) · cites this paper as [50]
In the citing paper
“It is now recognized that one of the major causes of aging and degenerative disease is the depletion of NAD+ in aging cells [87,88,89,90,91,92].”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [87]
In the citing paper
“Of note, the expression of Sirt1, Tfam and c-myc was also increased in Parib treated muscles (Figure S3K), which indicates that a recently identified SIRT1-dependent pathway (Gomes et al., 2013) by which NAD+ controls metabolic health might also be at play.”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Gomes et al., 2013
In the citing paper
“Gomes et al. reported that intraperitoneal injection of 500 mg/kg/day nicotinamide mononucleotide for 7 days could reverse muscle atrophy in aged C57BL/6J mice by decreasing the expression of MAFbx and MuRF1 [69].”
From Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy (2021) · cites this paper as [69]
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- Minamishima, 2008, Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure, Blood, 111, 3236, 10.1182/blood-2007-10-117812 · DOI · Paper page
Cited by
Sorted by citations
Ageing as a risk factor for neurodegenerative disease
Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0244-7 · Cited by 3,310
Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648
NAD+ metabolism and its roles in cellular processes during ageing
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00313-x · Cited by 1,617
The mitochondrial basis of aging
Sun, N., Youle, R. J., & Finkel, T. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.01.028 · Cited by 1,441
NAD+ and sirtuins in aging and disease
Imai, S.-I., & Guarente, L. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.04.002 · Cited by 1,481
Metadata
- Authors
- Gomes, A. P., Price, N. L., Ling, A. J. Y., Moslehi, J. J., Montgomery, M. K., Rajman, L., White, J. P., Teodoro, J. S., Wrann, C. D., Hubbard, B. P., Mercken, E. M., Palmeira, C. M., de Cabo, R., Rolo, A. P., Turner, N., Bell, E. L., & Sinclair, D. A.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- UNSW Sydney (AU)
- Centro de Neurociências e Biologia Celular (PT)
- National Institutes of Health (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Sinclair, David A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 155
- Issue
- 7
- Pages
- 1624-1638
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4076149
- OpenAlex
- W2171748049
- Cited by
- 1,482
- References
- 68
- Citations by year
- 2026: 99 · 2025: 114 · 2024: 115 · 2023: 115 · 2022: 148 · 2021: 125 · 2020: 133 · 2019: 110 · 2018: 115 · 2017: 104 · 2016: 116 · 2015: 83 · 2014: 98 · 2013: 1
- FWCI
- 46.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (R37AG028730, R01AG028730)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- pseudohypoxia, mitochondrial-nuclear communication, aging, mitochondrial dysfunction, HIF-1α, SIRT1, Warburg effect, mitochondrial biogenesis
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Aging, Animals, Cell Nucleus, Mitochondria, NAD, Oxidative Phosphorylation, Transcription Factors, Reactive Oxygen Species, Muscle, Skeletal, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, AMP-Activated Protein Kinases, Sirtuin 1
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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