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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NAD+ declines with age in several tissues, linking NAD to both senescence and aging.
“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
In Results, under “Nuclear NAD+ Levels Regulate Mitochondrially Encoded Genes” (page unavailable), the paper reports less total NAD+ in the skeletal muscle of elderly mice and describes an overall age-related decline. It does not establish the citing sentence’s more specific claim that NAD+ declines in several tissues. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHIF1α has been shown to increase during aging affecting nuclear-mitochondrial communication.
“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
Metformin's direct activation of SIRT1 may help combat age-related mitochondrial dysfunction attributed to reduced SIRT1 activity leading to downregulation of TFAM and declines in NAD+.
“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
NAD+ is a vital redox cofactor for metabolism and ATP production and a key substrate for at least four enzyme families involved in healthspan and longevity.
“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
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 Gomes et al., 2013
NAD+ depletion induces a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication, contributing to age-related mitochondrial decline.
“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
NMN enhances mitochondrial function in various organs, including skeletal muscle, kidney, liver, heart, eyes, brain and the cardiovascular system, and can mitigate oxidative stress in the vasculature, including improvements in neurovascular coupling responses in the aged cortex.
“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]
NMN has a significant effect on improving disease conditions and reducing age-related physiological decline.
“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]
This age-related NAD+ decline causes mitochondrial dysfunction and metabolic abnormalities.
“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
Levels of NAD+ and its precursors fall during chronological aging and in progeroid syndromes.
“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
NAD+ availability and NAD+-dependent enzyme activity regulate many of these aging phenotypes.
“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
Mitochondrial decline with age can be reversed and plays a part in aged tissue dysfunction.
“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]
SIRT1 modulates the process by which reduced NAD+ contributes to mitochondrial decay in aging skeletal muscle.
“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]
An imbalance between nuclear- and mitochondrial-encoded respiratory chain subunits caused by declining nuclear NAD+ disrupts oxidative phosphorylation in aged mice.
“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]
Boosting nuclear NAD+ restores mitochondrial activity in aged mice.
“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]
Reduced NAD+ levels contribute to mitochondrial decay in aging skeletal muscle.
“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 aged mice, loss of SIRT1 activity via declining NAD+ increases HIF-1α activity linked to mitochondrial dysfunction and oxidative phosphorylation changes.
“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
Nuclear-mitochondrial communication is a key determinant of longevity in animals.
“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
Mitochondrial dysfunction and low NAD+ levels are hallmarks of skeletal muscle ageing and sarcopenia.
“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 rodents, the age-dependent decline in NAD+ levels decreases SIRT1 activity, ultimately affecting mitochondrial homeostasis.
“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 22-month-old mice, nicotinamide mononucleotide restores NAD+ levels and markers of mitochondrial decline during ageing, reduces age-associated body weight gain, and increases energy metabolism and physical activity.
“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]
Reduced NAD+ levels in skeletal muscle of aged or Nampt deficient mice alter mitochondrial bioenergetics and impair muscle mass, strength and endurance.
“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]
Low NAD+ is a causal mechanism for mitochondrial perturbations in age-related pathologies in model organisms.
“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]
Depletion of NAD+ in aging cells is one of the major causes of aging and degenerative disease.
“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]
Sirt1, Tfam and c-myc expression increased in Parib-treated muscles.
“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
Intraperitoneal injection of 500 mg/kg/day nicotinamide mononucleotide for 7 days could reverse muscle atrophy in aged C57BL/6J mice by decreasing expression of MAFbx and MuRF1.
“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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CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels
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BackgroundReconsidering the Role of Mitochondria in Aging
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P7C3 Neuroprotective Chemicals Function by Activating the Rate-Limiting Enzyme in NAD Salvage
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Autophagy in Cardiovascular Aging
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Self-citation
- 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 · 2012: 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 › 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
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