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NAD+ metabolism and its roles in cellular processes during ageing

Nature Reviews Molecular Cell Biology volume 22, pages 119–141 (2021)Cite this article

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Abstract

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.

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Fig. 1: NAD+ metabolism.
Fig. 2: Three main classes of NAD+-consuming enzymes.
Fig. 3: NAD+ metabolism in ageing.
Fig. 4: Therapeutic approaches to restore NAD+ levels and their impact on health.

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Acknowledgements

This Review was supported by NIH grant R24DK085610 (E.V.) and Buck Institute for Research on Aging intramural funds (E.V.). A.J.C. is a recipient of a University of California President’s Postdoctoral Fellowship at the University of California, San Francisco, and is also supported by an NIH T32 training grant (3T32AG000266-19S1).

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Author notes

  1. These authors contributed equally: Anthony J Covarrubias, Rosalba Perrone, Alessia Grozio.

Authors and Affiliations

  1. Buck Institute for Research on Aging, Novato, CA, USA

    Anthony J. Covarrubias, Rosalba Perrone, Alessia Grozio & Eric Verdin

  2. UCSF Department of Medicine, San Francisco, CA, USA

    Anthony J. Covarrubias & Eric Verdin

Authors
  1. Anthony J. Covarrubias
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  2. Rosalba Perrone
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  3. Alessia Grozio
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Contributions

All authors contributed to the research for and discussion, writing and review of the manuscript. A.J.C., R.P. and A.G. designed the figures and tables.

Corresponding author

Correspondence to Eric Verdin.

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Competing interests

E.V. is a scientific co-founder of Napa Therapeutics and serves on the scientific advisory board of Seneque. E.V., A.J.C. and R.P. receive research support from Napa Therapeutics. E.V. and A.G. receive research support from BaReCia. A.G serves as Chief Scientific Officer for Seneque USA and is one of the inventors on a patent (PCT/US18/46233) for the SLC12A8 nicotinamide mononucleotide transporter, whose applicant is Washington University in St. Louis and which has been licensed by Teijin Limited (Japan).

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Nature Reviews Molecular Cell Biology thanks J. Auwerx and M. Hirschey and T. Nakagawa for their contribution to the peer review of this work.

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Redox reactions

Oxidation–reduction chemical reactions that involve a transfer of electrons between two species.

Hydride

Formally, the anion of hydrogen (H−). The term is commonly used to describe a binary compound that hydrogen forms with other electropositive elements.

Kynurenic acid

A quinoline-2-carboxylic acid with a hydroxy group at C-4 (4-hydroxyquinoline-2-carboxylic acid). It is a product of the metabolism of l-tryptophan.

Picolinic acid

A pyridinemonocarboxylic acid in which the carboxy group is located at position 2 (pyridine-2-carboxylic acid). It is an intermediate in the metabolism of l-tryptophan.

Extracellular vesicles

Lipid bilayer-delimited particles of endosomal and plasma membrane origin that are released by cells in the extracellular milieu.

Insulin resistance

An impaired response to exogenous or endogenous insulin to increase glucose uptake and utilization, resulting in elevated levels of glucose in the blood.

Xeroderma pigmentosum

A rare autosomal recessive genetic disorder characterized by a defect in the DNA repair system (primarily in the nucleotide excision repair system) that causes increased sensitivity to the DNA-damaging effects of ultraviolet radiation.

Progeroid diseases

A group of rare genetic disorders characterized by clinical features typical of physiological ageing and mostly due to defects in the DNA repair system or in lamin A.

Ataxia telangiectasia

A rare autosomal recessive genetic disorder caused by defects in the ATM gene, which is involved in cell division and DNA repair. It is characterized by neurodegeneration, immunodeficiency, increased radiation sensitivity and cancer susceptibility.

Cockayne syndrome

A rare autosomal recessive genetic disorder caused by defects in the ERCC6 or ERCC8 gene, which is involved in DNA repair. It is characterized by severe photosensitivity, neurodegeneration and premature ageing.

Hormesis

A biphasic dose response to an agent characterized by a stimulatory or beneficial effect at low dose and an inhibitory or toxic effect at high dose.

AKT

A serine/threonine-specific protein kinase that participates in multiple signalling pathways related to metabolism, cell survival, motility, transcription and cell cycle progression.

K m

Michaelis–Menten constant representing the substrate concentration at which the reaction is half the maximum velocity (Vmax) in the Michaelis–Menten enzymatic kinetic model.

V max

The maximum reaction rate achieved by the system at saturated substrate concentration in the Michaelis–Menten enzymatic kinetic model.

Ectoenzymes

Enzymes located on the outer surface of a cell’s membrane with their catalytic site available to the exterior environment of the cell.

Transmembrane protein with a type II orientation

Integral cell membrane protein with the amino terminus on the cytoplasmic side and the carboxy terminus on the extracellular side of the membrane. The transmembrane domain is located close to the amino terminus. Type III transmembrane proteins show an opposite orientation.

Glycophosphatidylinositol-anchored protein

Soluble protein attached by a glycolipid anchor (glycophosphatidylinositol) to the cell membrane.

Paneth cells

Highly specialized epithelial cells located in the small intestine secreting antimicrobial peptides and proteins.

Inflammageing

Defined as the low-grade chronic inflammation and immune cell dysregulation/exhaustion that occurs gradually during the ageing process. Inflammageing is emerging as a key causal factor for many age-related diseases.

NLRP3 inflammasome

A multiprotein complex made up of the proteins ASC, NLRP3 and caspase 1 that is activated in response to pathogens or sterile cell and tissue damage. When activated, the complex leads to the cleavage of the proforms of the cytokines IL-1β and IL-18, which themselves become activated and secreted to further amplify inflammation and immune responses.

Virtual memory T cells

A subpopulation of CD8+ T cells that have a memory-like phenotype (semidifferentiated) but are never been exposed to a foreign antigen (antigen naive).

Regulatory T cells

A subpopulation of CD4+ T cells that modulate the immune system, suppressing the immune response and maintaining tolerance to self-antigens.

Immune checkpoint

Molecules present on the surface of different cell types (that is, T cells, antigen-presenting cells and cancer cells) that regulate the immune response via inhibitory or activating immune signalling pathways.

Senolytics

Agents that target and eliminate senescent cells.

Wallerian degeneration

An active process of degeneration that occurs after any lesion or interruption of axons of neurons that ultimately leads to cell death.

Microglia

Type of glial cell located throughout the brain and spinal cord that functions as a resident macrophage and is the first and main form of active immune defence in the central nervous system.

Astrocytes

Highly specialized star-shaped glial cells located in the brain and spinal cord and involved in several processes, including support of the blood–brain barrier, provision of nutrients to neurons, repair and scarring following injury, and facilitation of neurotransmission

α-Amino-β-carboxymuconate ε-semialdehyde decarboxylase

In de novo NAD+ biosynthesis, it is the enzyme that catalyses the decarboxylation of α-amino-β-carboxymuconate ε-semialdehyde to α-aminomuconate ε-semialdehyde.

Flavonoid

A member of a class of polyphenolic secondary metabolites found in plants.

AMPK

5′-AMP-activated protein kinase, an enzyme that on changes in the ATP:AMP ratio phosphorylates downstream targets to redirect metabolism towards increased catabolism and decreased anabolism.

mTOR–p70S6K

Signalling pathway that involves the serine/threonine protein kinase mTOR and the mitogen-activated serine/threonine protein kinase p70S6K and regulates protein synthesis and cell proliferation, differentiation and survival.

ERK

Extracellular signal-regulated kinase involved in cell growth by controlling many proteins required in translation regulation.

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Covarrubias, A.J., Perrone, R., Grozio, A. et al. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 22, 119–141 (2021). https://doi.org/10.1038/s41580-020-00313-x

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