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Review
. 2014 Jul;30(7):271-86.
doi: 10.1016/j.tig.2014.04.007. Epub 2014 May 28.

Sirtuins: guardians of mammalian healthspan

William Giblin  1 , Mary E Skinner  2 , David B Lombard  3
Affiliations
Review

Sirtuins: guardians of mammalian healthspan

William Giblin et al. Trends Genet. 2014 Jul.

Abstract

The first link between sirtuins and longevity was made 15 years ago in yeast. These initial studies sparked efforts by many laboratories working in diverse model organisms to elucidate the relations between sirtuins, lifespan, and age-associated dysfunction. Here, we discuss the current understanding of how sirtuins relate to aging. We focus primarily on mammalian sirtuins SIRT1, SIRT3, and SIRT6, the three sirtuins for which the most relevant data are available. Strikingly, a large body of evidence now indicates that these and other mammalian sirtuins suppress a variety of age-related pathologies and promote healthspan. Moreover, increased expression of SIRT1 or SIRT6 extends mouse lifespan. Overall, these data point to important roles for sirtuins in promoting mammalian health, and perhaps in modulating the aging process.

Keywords: NAD(+); SIRT1; SIRT3; SIRT6; age-associated disease; aging; longevity; mitochondria.

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Figures

Figure 1
Figure 1. Lifespan extension in sirtuin transgenic mouse models
A. SIRT1 overexpressed in the dorsomedial and lateral hypothalamic nuclei (DMH/LH) extends lifespan of both male and female mice by upregulating expression of the orexin type 2 receptor (OX2R), through deacetylation of the Nk2 homeobox 1 transcription factor (NKX2-1). B. Whole-body SIRT6 overexpression increases lifespan in male mice by inhibition of the insulin-like growth factor 1 (IGF-1) signaling cascade. Affected downstream effectors are indicated: phosphorylated AKT, (pAKT), phosphorylated forkhead box protein O1 and O3 (pFOXO1 and pFOXO3), and phosphorylated S6 kinase (pS6). IGFBP1, IGF-1 binding protein 1.
Figure 2
Figure 2. Sirtuins as guardians of mammalian healthspan
SIRT1, 3, and 6 attenuate multiple age-associated diseases as indicated. Tumor suppressor and oncogenic properties have been reported for each of these proteins. SIRT1 and SIRT6 overexpression extend longevity in mice.
Figure 3
Figure 3. Representative major sirtuin interactors/substrates
Examples of sirtuin protein interacting partners or substrates relevant to pathways outlined in the text.
See this image and copyright information in PMC

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