Xuan Sun [1,2], Benjamin Cao [1,2], Shen Y Heazlewood [1,2], Brenda Williams [1,2], Chad K Heazlewood [1,2], Christian Nefzger , Jose Polo  and Susan K Nilsson [1, 2]
 Manufacturing, Commonwealth Scientific and Industrial Research Organization (CSIRO), Melbourne, Australia
 Australian Regenerative Medicine Institute (ARMI), Monash University, Melbourne, Australia
The maintenance of blood production depends on the ability of haematopoietic stem cells (HSC) to regenerate and differentiate into all mature blood cell lineages. With age, HSC lose their regenerative abilities and quiescence, becoming metabolically more active, resulting in an expansion of the HSC pool and a coinciding skewed lineage differentiation. Ultimately this commonly leads to the development of anaemia, bone marrow failure or leukaemia. Hence, rejuvenation agents that reverse or prevent the aging of HSC would not only have a tremendous socio-economic impact but also allow healthy aging. Nicotinamide adenine dinucleotide (NAD) is a vital cofactor in cell metabolism, with multiple recent studies reporting the aging of a variety of tissue stem cells being associated with a coinciding decline of NAD. We therefore reasoned the administration of the NAD precursor (Nicotinamide riboside, a specific form of vitamin B3, vB3), would rejuvenate aged HSC in vivo. Indeed, vB3 treatment of aged mice reduced the enlarged murine HSC pool, reversed myeloid lineage skewing, improved HSC homing and normalised HSC metabolism. Serendipitously, we also identified a pronounced cobalt (vitamin B12, vB12) deficiency in aged HSC. Similarly to vB3, vB12 is an essential cofactor for a number of metabolic processes and its levels decline with age in many tissues. Strikingly, repletion of vB12, also resulted in profound functional improvements in aged haematopoiesis, including reducing the enlarged HSC and progenitor pool, restoring HSC quiescence, reversing myeloid lineage skewing and correcting the age-associated myeloid-biased lineage distribution post-transplant. Together, our data reveals critical consequences for vB3 and vB12 depletion in HSC aging, and suggests treatment using these two nutraceuticals either individually or in combination, both with excellent preclinical/clinical safety profiles, could be effective approaches to support healthy haematopoietic aging and prevent age-associated diseases.