A number of studies have suggested that pharmacological compounds such as resveratrol, which activate (among others) SIRT1, can improve longevity in rodents and also metabolic function in obese rodents and humans. However, recent data (see attached) suggests that the over-expression of SIRT1 does not improve skeletal muscle insulin sensitivity, does not have an additive effect to caloric restriction and has no significant effect whole body metabolism. Additionally a number of reports have questioned the specificity of resveratrol as a SIRT1 activator which leads to the question of how relevant is SIRT1 in the physiological regulation of insulin responses and metabolic function?
David:
Thanks for this intriguing question.
I would note however that this data (the UCSD study from White et al. [1]) is not compelling given some methodological concerns that emerged upon my critical appraisal. Essentially what was tested was an insulin-normal model in lean young mice, but this does not in any way exclude a positive effect from muscle SIRT1 overexpression in what I would consider a far more clinically relevant insulin-resistant model; indeed, the clinical relevance and applicability - should these results ever be confirmed with true human clinical data and not just in preclinical animal studies - of absence of muscle SIRT1 overexpression is wholly unclear when observed in the absent of any significant insulin resistance. And even more critically, the UCSD White et al. results stand against several lines of contradicting evidence, as for instance the conclusion drawn in the Chinese Academy of Sciences study [2] that increased expression of SIRT1 did in fact improved insulin sensitivity, especially under insulin-resistant conditions, and with resveratrol apparently acting as a SIRT1 activator, enhancing insulin sensitivity both in vitro in a SIRT1-dependent manner and also preventing high-fat-diet-induced insulin resistance in vivo.
Furthermore, germline overexpression of SIRT1 was observed in the UCSD study (acknowledged by the investigators), in addition to large-scale (~150-fold) SIRT1 overexpression, leaving open the possibility that beneficial insulin modulation may be preempted under such specialized conditions of chronic SIRT1 overexpression and/or aberrantly large SIRT1 overexpression. White and co-authors try to counter this, implausibly, by noting that a previous Columbia University study [3] found that muscle insulin action was unaffected by two- to threefold SIRT1 overexpression from germline, but that is clearly a vastly smaller magnitude of SIRT1 overexpression (2X - 3X) from that observed in the UCSD White study, running at ~150X-fold, and no extrapolation therefore can be legitimate here.
In closing let me add that it's beyond the scope of this brief response (the last time I reviewed these issue late last year, the review ran to 85+ pages with 28 pages of references (300+) to enter authoritatively into (1) the association of SIRT1 with caloric restriction, (2) with whole-body metabolic status, and (3) whether resveratrol exerts true SIRT1 molecular activation, but I am not based on the preponderance of evidence convinced that these associations have been plausibly challenged by methodologically robust data (multiple reviews I critically appraised conclude the opposite), nor that SIRT1 activation is not observable in resveratrol operation (especially when we differentiated dose-dependent effects as per the recent Harvard/NIH study [4], among others). But that's another story. In the here and now, under critical review the UCSD study results do not materially affect the balance of evidence given unresolved methodological concerns, and the presence of a non-trivial body of contradicting data.
1. White AT, McCurdy CE, … Schenk S. Skeletal muscle-specific overexpression of SIRT1 does not enhance whole-body energy expenditure or insulin sensitivity in young mice. Diabetologia 2013 Apr 19.
2. Sun C, Zhang F, Ge X, et al. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab 2007; 6(4):307-19.
3. Banks AS, Kon N, Knight C, et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 2008; 8(4):333-41.
4. Price NL, Gomes AP, Ling AJ, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 2012 May 2; 15(5):675-90.
There was a similar paper published by Schenk in 2011 in J Clin Invest reporting an increase in muscle insulin sensitivity and the reported influence of SIRT1 expression during caloric restriction. There are also data from Timmons' group (2007) indicating that SIRT1 may have a role in mitochondrial biogenesis in brown adipose tissue differentiation and maturation.
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