Genetic overexpression of protein deacetylase Sir2 increases longevity in a variety of lower organisms, [this is of course contested -MR] and this has prompted interest in the effects of its closest mammalian homologue, Sirt1, on ageing and cancer. We have generated transgenic mice moderately overexpressing Sirt1 under its own regulatory elements (Sirt1-tg). ["These two lines, named here as Sirt1-tgA15 and Sirt1-tgB, overexpress ~3-fold Sirt1 mRNA across all tissues tested and present detectably higher levels of Sirt1 protein, as well as an increase in hepatic Sirt1 activity measured by the lower levels of acetylated lysine 310 of p65RelA, a known target of Sirt1 deacetylase activity. In agreement with their similar levels of Sirt1 upregulation, both transgenic lines displayed similar phenotypes regarding protection from HFD [high-fat (and very high-Calorie] diet], such as, decreased adipose tissue inflammation, improved glucose tolerance, and protection from hepatic steatosis, as well as increased sensitivity to lipopolysaccharide shock under standard diet."]
Old Sirt1-tg mice present lower levels of DNA damage, decreased expression of the ageing-associated gene p16Ink4a, a better general health and fewer spontaneous carcinomas and sarcomas. ["Detailed histopathological analyses of old moribund mice revealed a lower incidence of malignant tumours in Sirt1-tg mice, compared with WT mice of both lines (Fig. 1b). Remarkably, the suppressive effect of Sirt1 on malignant tumours was restricted to carcinomas and sarcomas (mostly osteosarcomas), whereas it had no effect on the incidence of lymphomas and histiocytic lymphomas (the latter also known as histiocytic sarcomas) (Fig. 1c). It is important to mention that most spontaneous carcinomas and sarcomas were in general of small size (as was the case of liver or lung carcinomas) or affected non-vital organs (such as Harderian gland carcinomas in the eyes or osteosarcomas in the limbs). Therefore, despite their malignancy, most carcinomas and sarcomas were at a stage of dissemination that is unlikely to be the primary cause of death. This is in contrast to spontaneous lymphomas, which had similar incidences in WT and tg mice, and were highly aggressive and the likely cause of death. ... Additional indicators of fitness at old age were obtained by measuring skin regeneration (wound-healing assay, Fig. 2c) and neuromuscular coordination (tightrope assay, Fig. 2d), both of which suggested a better performance by Sirt1-tgA mice (no effect at this level was detected in Sirt1-tgB mice [the other])."]
These effects, however, were not sufficiently potent to affect longevity.
... [In] a metabolic syndrome-associated liver cancer model ... Sirt1-tg mice show a reduced susceptibility to liver cancer and exhibit improved hepatic protection from both DNA damage and metabolic damage.
["Conceivably, the lack of effect of Sirt1 on spontaneous lymphomas could mask a putative effect of Sirt1 on longevity."] Together, these results provide direct proof of the anti-ageing activity of Sirt1 in mammals and of its tumour suppression activity in ageing- and metabolic syndrome-associated cancer.(1)
Of course, they do not "provide direct proof of the anti-ageing activity of Sirt1 in mammals" absent an effect on lifespan. Still, the findings are intriguing, especially to the extent that there is overlap with some of the observations in nonobese resveratrol-fed animals.(2) As (1) notes,
it is also worth to point out the similarities between the phenotypes of our Sirt-tg mice and the reported effects of the small natural compound resveratrol on mice, which upregulates Sirt1 activity [this of course is hotly contested -MR], perhaps indirectly through effects mediated by AMPK. Mice chronically fed with resveratrol are protected from metabolic syndrome induced by HFD, and present improved healthy ageing without affecting longevity. Interestingly, although resveratrol did not protect from spontaneous cancers, our Sirt1-tg mice were partially protected from these cancers.(1)
The effects on the cancer spectrum are interesting. In the resveratrol study, they found
resveratrol treatment did not significantly alter the distribution of pathologies in SD groups. This included neoplasias, despite the potency of resveratrol against implanted or chemically induced tumors ... This may be related to the fact that the vast majority of these cases were lymphomas, a tumor type for which the efficacy of resveratrol has not been thoroughly assessed, and that is thought to be triggered mainly by endogenous retroviruses in mice (2)
... but they don't provide any details on the distribution of cancers. Here, by contrast, they do report a reduction in some classes of tumors in SIRT1-TG animals -- just mostly not apparently fatal ones, and not of lymphomas. In the resveratrol study, the authors hypothesized that
It may also be that resveratrol slows the general age-related decline but does not impact the specific causes of death in these mice. Indeed, resveratrol did not suppress lymphoma, a major cause of mortality in C57BL/6 mice. (2)
They were on rather weak grounds in that case, having shown no reduction in overall cancer, other cancer types, or any class of gross pathology; this report is on stronger grounds in hypothesizing that "the lack of effect of Sirt1 on spontaneous lymphomas could mask a putative effect of Sirt1 on longevity." The background strain is 87.5% C57BL/6 (and 12.5% CBA), as with the resveratrol study, and while very longevous and robust, the C57BL/6 does indeed quite commonly die of lymphomas.
Also interesting is the fact that, while resveratrol did not extend the lifespan of normal, healthy mice at either low, high, or ultra-high dose:
Effects of resveratrol on mice fed Standard Diet (SD) ... Later, additional groups of mice were given a higher dose of resveratrol along with the standard or HC diets (2400 mg/kg of food, SDHR, or HCHR). ... We have also tested the effect of a higher dose of resveratrol beginning at 12 months of age (SDHR) on lifespan, and again found that longevity was not significantly affected". From Pearson et al, 2008.
... despite the fact that it partly normalized the shortened lives of obese, diabetic mice fed diets loaded with saturated and trans-fat and sugar (HCLR, HCR, HCHR) (I hope that's not you
), one other group of mice did seem like they might have gained some lifespan from resveratrol: the group on mild (10-15%) every-other-day fed (EOD) CR and given the low (EODLR), but not the high (EODR) resveratrol dose:
CR of course profoundly represses carcinogenesis, and is quite effective in reducing mortality from lymphomas in these mice. If resveratrol, like extra SIRT1 expression, is having some sort of fairly extensive "anti-aging" benefit, but is not giving sufficiently robust protection against cancers (other than some mostly nonfatal carcinomas and osteosarcomas -- and mostly osteosarcomas, at that, which are rare causes of death in mice as in (wo)men), then giving additional cancer protection through mild CR could, hypothetically, give the 'space' required for those "anti-aging" effects to impact lifespan.
Looking at the apparent health effects, they are even more ambiguous. Both interventions are said to have effected a deceleration of age-related bone mass loss, but the effects of resveratrol were mostly nonsignificant trends. One might reasonably expect that at least some mechanisms of maintaining bone mass (if anabolic) would increase osteosarcoma risk, as Forteo apparently does. A lifelong antiresorptive effect seems less likely to slow down bone degeneration, and indeed to possibly increase fracture risk, though there was no test of bone strength in this study. In the resveratrol case, any effect on bone mass might have been a simple phytoestrogenic effect, but we can rule that out here.
Meanwhile, both interventions are said to have led to improved coordination -- but only 1 of 2 transgenic models did so, and while there was “a pronounced and statistically significant improvement at 21 and 24 months [in animals fed a normal diet and given the higher dose of resveratrol] indicating that resveratrol improves balance and motor coordination in aged animals,”(2) this was only true in 1 diet group, and at 1 dose. Is this just a type II error from testing too many combinations (3 diets, 2 (or 3) doses), or a hard-to-detect effect, or what?
Or maybe all of this is too clever by half. As I've reminded folks elsewhere,
Functionally, remember that "Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction" (ref) ... doesn't fully replicate CR-induced gene expression changes (ref). Heck, it's not even clear that the stuff does any good in yeast (where the whole hype got started) (ref); nor in Drosophila elegans (note that Partridge's group is possibly the most experienced lab in the world in doing lifespan studies in Drosophila) (ref); nor in another (tephritid) species of fruit flies ((ref): there may have been a marginal effect in flies fed 1 of the 24 different diet combinations, but I'm skeptical of that result, and IAC there was no effect in the other 23 diets); nor in C. elegans (ref)
It would be delightful to see both SIRT1-TG and resveratrol this tested with stronger CR ... And of course, this brings us back to the vexed, still-contested issue of whether resveratrol increases SIRT1 activity in vivo, after oral administration. Not to mention the fact that the reported bioavailability of oral resveratrol is all over the damned map in rodent studies, and even within human studies the intersubject variability in resveratrol per se is absolutely huge: in (3), Cmax for resveratrol at 5000, 1000, 2500, or 5000 mg, in ng/mL with % coefficient of variation in brackets, were 72.6 (48.9), 117.0 (73.1), 268.0 (55.3), and 538.8 (72.5) -- and that's within one study, with a single dose form and administration protocol. And beyond the parent molecule what exactly are the effects and pharmacological effects of the many resveratrol metabolites, present at much higher levels and at less variabiity, and the interspecies differences in which are produced in mice vs. in humans?
It's still rather crazy to take that crap shoot with your own body -- but as with any highly unpredictable, high-stake gambling, it can be most engaging to watch ...
References
1. Daniel Herranz, Maribel Muñoz-Martin, Marta Cañamero, Francisca Mulero, Barbara Martinez-Pastor, Oscar Fernandez-Capetillo.
Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer.
Nature Communications 1(3)
Received 02 November 2009; Accepted 26 February 2010; Published 12 April 2010
doi:10.1038/ncomms1001
2. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R.
Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span.
Cell Metab. 2008 Aug;8(2):157-68.
PMID: 18599363 [PubMed - as supplied by publisher]
3. Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1246-52. PubMed PMID: 17548692.
