Sirtuins are connected to the upregulation of cellular stress response mechanisms triggered by, for example, calorie restriction. Given the failure of past attempts to intervene in aging at the point of sirtuin 1, it may be that the influence of sirtuins on the pace of aging simply isn't large enough to be useful. That said, work on other sirtuins, such as sirtuin 6 and to a lesser degree sirtuin 3, have produced somewhat better results in mice. Still, stress response upregulation as a whole is demonstrably far more influential on life span in short-lived species such as mice than it is in long-lived species such as humans. Calorie restriction can extend maximum life span in mice by 40%, but certainly does no such thing in humans. This should tell us that we must look elsewhere for means of extending the healthy human life span by decades.
Sirtuins may counteract organismal aging by altering the pattern of cellular stress response to generate much less disruption of tissue homeostasis. The alteration of cellular stress response pattern by sirtuins comprises (1) inhibition of apoptosis, (2) promoting DNA damage repair instead of apoptosis or induction of cellular senescence, (3) antioxidative action through activation of MnSOD, (4) preventing carcinogenesis through acting as tumor suppressor proteins, (5) inhibition of unnecessary inflammatory response/inflammaging through inactivation of NF-kB, and (6) preventing cellular senescence and senescence-associated secretory phenotype (SASP) through mitochondrial protection and promoting DNA damage repair.
All the effects listed above combined may prevent disruption of tissue homeostasis - directly responsible for organismal aging in vertebrates while being itself a distant derivative of a prolonged, inappropriate pattern of cellular response to accidental damage of the biostructure. The mechanisms discussed in this review describe how exactly sirtuin-dependent modifications of the cellular stress response can slow down aging at the tissue level. Thus, sirtuins, especially SIRT1, SIRT3, and SIRT6, can modify cellular stress response to promote maintenance of tissue homeostasis and thus slow down phenotypic aging at the organismal level.