Ann Lab Med.  2018 Sep;38(5):395-401. 10.3343/alm.2018.38.5.395.

Rejuvenating Aged Hematopoietic Stem Cells Through Improvement of Mitochondrial Function

• Moon J
• Kim HR
• Shin MG

• KMID: 2434727
• DOI: http://doi.org/10.3343/alm.2018.38.5.395

Abstract

Mitochondria are the powerhouses of the cell as well as the primary site of hematopoiesis, which also occurs in the cytoplasm. Hematopoietic stem cells (HSCs) are characterized by a very high turnover rate, and are thus considered to be relatively free from the age-related insults generated by mitochondria. However, HSCs are also subject to these age-related insults, including the incidence of myeloid proliferative diseases, marrow failure, hematopoietic neoplasms, and deterioration of the adaptive human immune system. Recently, NAD⁺ dietary supplements, known as niacin or vitamin B₃, including tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD⁺ precursor nicotinamide riboside, have been shown to play a role in restoring adult stem cell function through the amelioration of mitochondrial dysfunction. This insight motivated a study that focused on reversing aging-related cellular dysfunction in adult mouse muscle stem cells by supplementing their diet with nicotinamide riboside. The remedial effect of nicotinamide riboside enhanced mitochondrial function in these muscle stem cells in a SIRT1-dependent manner, affecting cellular respiration, membrane potential, and production of ATP. Accordingly, numerous studies have demonstrated that sirtuins, under nuclear/mitochondrial control, have age-specific effects in determining HSC phenotypes. Based on the evidence accumulated thus far, we propose a clinical intervention for the restoration of aged HSC function by improving mitochondrial function through NAD⁺ precursor supplementation.

Keyword

Hematopoietic stem cells; Aging; Mitochondrial dysfunction; Restoration; NAD⁺ precursors

MeSH Terms

Adenosine Triphosphate
Adult
Adult Stem Cells
Aging
Animals
Bone Marrow
Cell Respiration
Cytoplasm
Diet
Dietary Supplements
Hematologic Neoplasms
Hematopoiesis
Hematopoietic Stem Cells*
Humans
Immune System
Incidence
Membrane Potentials
Mice
Mitochondria
Niacin
Niacinamide
Phenotype
Sirtuins
Stem Cells
Tryptophan
Vitamins
Adenosine Triphosphate
Niacin
Niacinamide
Sirtuins
Tryptophan
Vitamins

Figure

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  Fig. 1 The heme biosynthetic pathway in the mitochondria and cytoplasm. Heme synthesis starts in the mitochondria and then returns to the mitochondria through several cytoplasmic steps.Abbreviation: ALA, aminolevulinic acid.

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  Fig. 2 Proposed molecular mechanisms of hematopoietic stem cell (HSC) aging and related disease phenotypes. HSC aging is caused by the alteration of nuclear and mitochondrial genomes, as well as transcriptome and epigenetic changes, resulting in the occurrence of aging-related hematopoietic diseases.Abbreviations: mtDNA, mitochondrial DNA; ROS, reactive oxygen species.

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  Fig. 3 Schematic representation of the research objectives and hypothesis: restoration of aged hematopoietic stem cell (HSC) function through improving mitochondrial function.

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  Fig. 4 Aging syndrome of a hematopoietic stem cell (HSC) and proposed restoration strategy. In old animals, aging may cause an NAD+ deficit by activating poly (ADP-ribose) polymerases (PARPs). The NAD+ shortage then decreases the activity of sirtuins, which are anti-aging proteins, thereby promoting the aging cycle. Nicotinamide riboside (NR) replenishes NAD+ and corrects the cycle to enhance stem cell maintenance, tissue function, and the unfolded protein response (UPR).

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  Fig. 5 Possible molecular mechanisms and role of NAD+ precursors in restoring hematopoietic stem cell (HSC) function. Aged HSC function might be recovered through increasing mitochondrial function using NAD+ precursors.Abbreviations: AMPK, 5′ adenosine monophosphate-activated protein kinase; NAMPT, nicotinamide phosphoribosyltransferase; FOXO, forkhead box protein; SIRT1, sirtuin 1; Sir2, silent information regulator 2; NR, nicotinamide riboside; cADP, cyclic ADP; Nam, nicotinamide; Trp, tryptophan; Na, nicotinic acid; Na ADP, nicotinic ADP.

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