The human HSC expresses Sirtuin 4

Sirtuins have been described as master regulators of lifespan and associated with biochemical processes important for aging. We compared total transcription in HSC-like myeloid cells isolated from the bone marrow of humans to identify genes associated with aging and youth. We identified silencing of sirtuin 4 as a signature of the aged hematopoietic stem cell in humans. Contrarily, SIRT1 was activated concomitant with aging. SIRT4 changes were an important part of the senescence gene expression signature in vitro. Sirtuin family gene expression changes were associated with genes functioning in nicotinamide metabolism; SIRT4 repression was associated with induction of NAPRT, or nicotinate phosphoribosyltransferase. SIRT4 but not SIRT1 was a NANMT1 (nicotinamide nucleotide adenylyltransferase 1) co-regulated gene, supporting a functional importance for nicotinamide metabolism in sirtuin 4 biology. SIRT4 silencing was observed in a human pluripotent stem cells model of Parkinson's Disease resulting from mutation of the PARK2 gene. The data support a role for sirtuins in aging and degenerative disease processes associated with aging in humans.