Aging of hematopoietic stem cells (HSCs) has been largely described as one underlying cause of senescence of the immune-hematopoietic system (immunosenescence). A set of well-defined hallmarks characterizes aged HSCs contributing to unbalanced hematopoiesis and aging-associated functional alterations of both branches of the immune system. In this chapter, the contribution of sirtuins, a family of conserved NAD+ dependent deacetylases with key roles in metabolism, genome integrity, aging and lifespan, to immunosenescence, will be addressed. In particular, the role of SIRT6 will be deeply analyzed highlighting a multifaceted part of this deacetylase in HSCs aging as well as in the immunosenescence of dendritic cells (DCs). These and other emerging data are currently paving the way for future design and development of rejuvenation means aiming at rescuing age-related changes in immune function in the elderly and combating age-associated hematopoietic diseases.