NAD+ flux is maintained in aged mice despite lower tissue concentrations

Melanie R McReynolds; Karthikeyani Chellappa; Eric Chiles; Connor Jankowski; Yihui Shen; Li Chen; Hélène C Descamps; Sarmistha Mukherjee; Yashaswini R Bhat; Siddharth R Lingala; Qingwei Chu; Paul Botolin; Faisal Hayat; Tomohito Doke; Katalin Susztak; Christoph A Thaiss; Wenyun Lu; Marie E Migaud; Xiaoyang Su; Joshua D Rabinowitz; Joseph A Baur

doi:10.1016/j.cels.2021.09.001

NAD⁺ flux is maintained in aged mice despite lower tissue concentrations

Cell Syst. 2021 Dec 15;12(12):1160-1172.e4. doi: 10.1016/j.cels.2021.09.001. Epub 2021 Sep 23.

Authors

Melanie R McReynolds¹, Karthikeyani Chellappa², Eric Chiles³, Connor Jankowski⁴, Yihui Shen¹, Li Chen¹, Hélène C Descamps⁵, Sarmistha Mukherjee², Yashaswini R Bhat², Siddharth R Lingala², Qingwei Chu², Paul Botolin², Faisal Hayat⁶, Tomohito Doke⁷, Katalin Susztak⁷, Christoph A Thaiss⁵, Wenyun Lu¹, Marie E Migaud⁶, Xiaoyang Su³, Joshua D Rabinowitz⁸, Joseph A Baur⁹

Affiliations

¹ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Department of Chemistry, Princeton University, Princeton, NJ, USA.
² Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
⁴ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
⁵ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Department of Pharmacology, Mitchell Cancer Institute, College of Medicine, University of South Alabama, Mobile, AL, USA.
⁷ Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Department of Chemistry, Princeton University, Princeton, NJ, USA. Electronic address: [email protected].
⁹ Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: [email protected].

Abstract

NAD⁺ is an essential coenzyme for all living cells. NAD⁺ concentrations decline with age, but whether this reflects impaired production or accelerated consumption remains unclear. We employed isotope tracing and mass spectrometry to probe age-related changes in NAD⁺ metabolism across tissues. In aged mice, we observed modest tissue NAD⁺ depletion (median decrease ∼30%). Circulating NAD⁺ precursors were not significantly changed, and isotope tracing showed the unimpaired synthesis of nicotinamide from tryptophan. In most tissues of aged mice, turnover of the smaller tissue NAD⁺ pool was modestly faster such that absolute NAD⁺ biosynthetic flux was maintained, consistent with more active NAD⁺-consuming enzymes. Calorie restriction partially mitigated age-associated NAD⁺ decline by decreasing consumption. Acute inflammatory stress induced by LPS decreased NAD⁺ by impairing synthesis in both young and aged mice. Thus, the decline in NAD⁺ with normal aging is relatively subtle and occurs despite maintained NAD⁺ production, likely due to increased consumption.

Keywords: CD38; NAD; NADH; PARP; PARP1; SIRT1; aging; flux; mononucleotide; niacin; nicotinamide; redox; riboside; sirtuins.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging
Animals
Caloric Restriction
Mice
NAD* / metabolism
Niacinamide* / metabolism

Substances

NAD
Niacinamide

Abstract

Publication types

MeSH terms

Substances

Grants and funding