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Cell. 2018 Mar 22;173(1):74-89.e20. doi: 10.1016/j.cell.2018.02.008.

Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging.

Author information

1
Paul F. Glenn Center for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia; Paul F. Glenn Center for Science of Aging Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Paul F. Glenn Center for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Bldg. 421, Philadelphia, PA 19104, USA.
3
Paul F. Glenn Center for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
5
Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
6
Mitochondrial Bioenergetics Laboratory, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
7
Biological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, The University of New South Wales, Sydney, NSW 2052, Australia.
8
Paul F. Glenn Center for Science of Aging Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
9
Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Bldg. 421, Philadelphia, PA 19104, USA. Electronic address: zarany@pennmedicine.upenn.edu.
10
Paul F. Glenn Center for Science of Aging Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: leng@mit.edu.
11
Paul F. Glenn Center for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: david_sinclair@hms.harvard.edu.

Abstract

A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.

KEYWORDS:

NAD(+); aging; angiogenesis; endurance; exercise; hydrogen sulfide; ischemia; nicotinamide mononucleotide; sirtuins; skeletal muscle capillaries

PMID:
29570999
PMCID:
PMC5884172
[Available on 2019-03-22]
DOI:
10.1016/j.cell.2018.02.008
[Indexed for MEDLINE]
Free PMC Article

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