All:
I am a little bit suspicious about this, because (amongst other things) they don't give actual numbers on the survival data, the difference (even in relative terms) is small, and the sirtuin story has heretofore seemed to be done and dusted -- but maybe there's something in this, and if so it's really only the second time (after rapamycin). Interestingly, the benefits occurred without much of the evidence of souped-up metabolism observed in diabetic-obese mice given resveratrol.
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SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass.
Mercken EM1, Mitchell SJ, Martin-Montalvo A, Minor RK, Almeida M, Gomes AP, Scheibye-Knudsen M, Palacios HH, Licata JJ, Zhang Y, Becker KG, Khraiwesh H, González-Reyes JA, Villalba JM, Baur JA, Elliott P, Westphal C, Vlasuk GP, Ellis JL, Sinclair DA, Bernier M, de Cabo R.
... SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. ["6-month-old male C57BL/6J mice were placed on a standard AIN-93G diet (SD) supplemented with SRT2104 (100 mg/kg bodyweight) for the remainder of their lives, which yielded serum concentrations of 261.8±27.0 and 435.7±75.6 ng mL 1 in the morning and evening, respectively. [Remember, or know ye, that mice are nocturnal and eat most of their food (and thus would take most of their drug) in the evening rather than the morning -MR].
SRT2104 supplementation resulted in improved survival of SD-fed mice (v2 = 6.19 and P < 0.013) with an increase in mean lifespan of 9.7% (P < 0.05) and in maximum lifespan (defined as the 10th percentile) of 4.9% (P < 0.001) (Fig. 1A).
The immunosuppressant rapamycin has been recently shown to extend maximum lifespan of genetically heterogeneous male mice (Miller et al., 2011), and when started at 19 months of age, it also extends lifespan of male and female C57BL/6Nia mice (Zhang et al., 2014). Moreover, oral supplementation with the antidiabetic drug metformin leads to healthier and longer life in male mice (Martin-Montalvo et al., 2013). [Yeah -- not really longer life -MR]
The incidences of major pathologies detected at necropsy were reduced with SRT2104 treatment, most notably a trend toward lower prevalence of an enlarged heart and hepatocellular carcinoma with SRT2104, and a significant reduction in peri-renal fat (Table S1, Supporting information). Blinded histological analysis of tissues did not identify any serious pathology in SD mice, and there were no obvious differences between the two groups (Table S2). Consistent with this, biomarkers of liver injury or tissue breakdown were reduced or unchanged after SRT2104 supplementation (Table S3), further confirming that the dose was well tolerated with no obvious toxicity.
Interestingly, the increases in longevity induced by SRT2104 occurred despite similar bodyweights between SD-fed controls and treated animals (Fig. 1B). A reduction in percentage fat mass, but not lean body mass, was observed in SRT2104-treated mice (Fig. 1C and Table S4) despite no differences in food consumption (Figs 1D and S1A, Supporting information). Moreover, SRT2104 treatment did not affect spontaneous activity (Fig. 1E), energy expenditure (Fig. S1B), or respiratory exchange ratio (RER) of mice (Fig. S1C). "]
This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity associated with higher mitochondrial content and decreased inflammation.
Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans.
PMID: 24931715
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