An interesting role ascribed to Sir2 involves increased replicative lifespan, the number of cell divisions in which a mother cell can engage in its life [12
]. In the wormCaenorhabditis elegans
, in Drosophila melanogaster
and possibly in mammals, Sir2 family members are also involved in extending lifespan [42
]. One proposed mechanism to explain the relationship between Sir2 and lifespan is caloric restriction (CR), which increases lifespan in organisms from yeast to mammals [12
]. CR produces a more oxidative metabolic state, reflected by high levels of NAD+
. This in turn activates sirtuins and facilitates survival mechanisms such as senescence and apoptosis inhibition or activation of stress response pathways [44
Although a mechanistic link between cell senescence and aging is lacking, the implication of SirT1 in longevity and cell senescence of most organisms suggests an important role in the aging process. A cell is considered senescent either when it reaches growth arrest owing to telomere consumption (replicative senescence) or when abnormal oncogene expression alters cell physiology (premature senescence) [45
]. Data supporting a role for SirT1 in cell senescence are still correlative; senescent fibroblasts show a decrease in SirT1 expression [46
] and SirT1 overexpression can inhibit oncogene-induced senescence as a result of direct p53 deacetylation, which counteracts p53 hyperacetylation in oncogene-induced senescence [47
]. Many other observations support this idea, and other lines of investigation suggest an even more general role for SirT1 in aging and longevity [48
Given the effects of SirT1 on longevity, rejuvenation and in counteracting aging, the pharmaceutical, “nutraceutical” and cosmetic industries are interested in the development of small molecule SirT1 activators [49
]. Resveratrol, a natural compound present in traces in some red wines, has a strong sirtuin-activating effect. This polyphenol and related synthetic molecules have anti-aging activity and positive effects on aging-related disease, prolonging survival in mice [42
]. Clinical trials are under way to test the therapeutic potential of sirtuin activators in conditions such as type 2 diabetes [53
One of the more intriguing hypotheses about aging and age-related disease is that age-associated phenotypic alterations derive from the inability of resident stem cells to maintain tissue structure and function [54
]. This, and our current understanding of cell senescence as summarized above, suggest that the aging process could arise from loss or misfunction of self-renewal and/or differentiation potential in adult stem cell populations. Our data show a positive role for SirT1 in stemness by aiding in the silencing of differentiation genes, which suggests new potential explanations of its ability to extend lifespan and to avoid cell and organism senescence. SirT1 might in fact contribute to maintaining a “stemness-like” status in cell populations involved in tissue regeneration and to orchestrating their correct differentiation within tissue.
Although there is still a long path to walk before we reach full understanding of the complex and intriguing role of sirtuins, a small step has been made towards comprehension of SirT1 function in stem cells, with possible implications for the related fields of cancer and aging (). There is hope for a solution of present controversies, for new hypotheses, and for more fruitful application of this knowledge to cancer therapy, anti-aging and regenerative medicine, to improve the quality of daily life.
Representation of the possible connections of stemness, aging and cancer processes, mediated by SirT1.