Absence of effects of Sir2 over-expression on lifespan in C. elegans and Drosophila

By Camilla Burnett, S. Valentini, F. Cabreiro, M. Goss, Milán Somogyvári, M. Piper, Matthew P. Hoddinott, G. Sutphin, Vid Leko, J. McElwee and 13 more. Nature, 2011

633 citations recorded by the source corpus.

Overexpression of sirtuins (NAD+-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high-level sir-2.1 overexpression abrogated the longevity increase, but did not abrogate sir-2.1 overexpression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low-copy-number sir-2.1 overexpression also abrogated longevity. A Drosophila strain with ubiquitous overexpression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported, but was not long-lived relative to the appropriate transgenic controls, and nor was a new line with stronger overexpression of dSir2. These findings underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life-extending effect of dietary restriction on ageing in Drosophila has also been reported to be dSir2 dependent. We found that dietary restriction increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila.

Subfields: Aging, Geriatrics and Gerontology

View Paper: https://www.semanticscholar.org/paper/4a087d589bb3aaecc83cba07c40677e594ab7ebf

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Aging

1. L. Guarente
2. D. Sinclair
3. Johan Auwerx
4. C. Cantó
5. Hung-Chun Chang
6. S. Imai
7. R. Houtkooper
8. Bor Luen Tang

In Geriatrics and Gerontology

1. Johan Auwerx
2. D. Sinclair
3. L. Guarente
4. C. Cantó
5. S. Imai
6. R. Houtkooper
7. Bor Luen Tang
8. Keir J. Menzies

Citations in the corpus

• The hallmarks of aging. (2013, neutral): “1 or dSir2, respectively (Burnett et al., 2011).”
• The sirtuin SIRT6 regulates lifespan in male mice (2012, background): “However, the role of sirtuins in regulating worm and fly lifespan has recently become controversia”
• NAD+ and Sirtuins in Aging and Disease (2014, background): “Furthermore, previous results showing lifespan extension by Sir2 orthologs in worms and flies were called into question (15), bringing considerable debate around the importance of sirtuins in aging/ longevity control to the field of aging research.”
• Replicative and Chronological Aging in Saccharomyces cerevisiae (2012, neutral): “Although the data in worms and flies has recently been called into question (Burnett et al., 2011; Rizki et al., 2011; Viswanathan and Guarente, 2011), there seems to be general consensus that SirT1 interacts with important aging-related pathways in mammals, if not necessarily directly modulating th”
• Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans (2015, background): “In fact, some authors postulate that resveratrol cannot activate Sirt2 in vivo [111, 113] and that CR could increase fly lifespan regardless of Sirt2 activation [114].”
• The Role of Sirtuins in Antioxidant and Redox Signaling (2017, background): “GLP-1-(7-34)-amide Inhibits SIRT1 to stimulate pancreatic b-cell mass expansion.”
• Sirt1 and the Mitochondria (2016, background): “Sirt1’s role in longevity has been more extensively investigated in yeast and lower invertebrate models, and although the notion of Sirt1 as a longevity gene has a great deal of support, there were also controversies and evidence to the contrary (Burnett et al., 2011).”
• The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling (2013, background): “Although the role of SIRT1 or its homologs in lifespan extension under basal, un- stressed, conditions is subject of debate (Burnett et al., 2011; Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001; Viswanathan and Guarente, 2011), it holds a central position in healthspan regulation in the…”
• NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus (2015, background): “Despite some evidence disputing the link between sirtuins and the longevity effects of CR, or longevity in general (Burnett et al., 2011; Jiang et al., 2000; Lamming et al., 2005), most data agree that sirtuin activation in mammals delays the onset of agerelated degenerative processes (Herranz et…”
• Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. (2013, background): “Additionally, the importance of Sir2 orthologs for aging/longevity control in worms and flies has recently been called into question (Burnett et al., 2011).”
• The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice (2014, background): “Both BCAAs and insulin activate mTOR, and both are required for activation of pathways downstream of mTOR (Chotechuang et al., 2009).”