SRT 2104 extends survival of male mice on a standard diet and preserves bone and muscle mass

Abstract

Summary Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. 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.

Sirtuin1 (Sirt1) Promotes Cortical Bone Formation by Preventing β-Catenin Sequestration by FoxO Transcription Factors in Osteoblast Progenitors

“…This evidence along with the finding that cortical bone is unaffected in mice lacking Sirt1 in mature osteoblasts or osteoclasts (15) suggests that Sirt1 activity in osteoblast progenitors, as opposed to more mature cells, is responsible for the effects of Sirt1 on cortical bone. Importantly, we have previously shown that inducible germline deletion of Sirt1 in adult mice promotes the loss of cortical bone mass (11). Together with the results of the present report, this earlier finding supports the contention that the actions of Sirt1 in osteoblast progenitors are required not just for the acquisition of bone during growth, but for the maintenance of the skeleton throughout life as well.…”

“…Germline deletion or overexpression of Sirt1 decreases or increases bone mass, respectively (8,9). In line with this evidence, Sirt1 stimulators, such as resveratrol or SRT2140, prevent the loss of bone mass caused by unloading (10,11), ovariectomy (12), or aging (11,13). The effects of Sirt1 on bone are mediated, at least in part, via actions in cells of the osteoblast lineage.…”

Translating the Science of Aging into Therapeutic Interventions

“…Indeed, drugs have been discovered that enhance life span and health span in rodents. These include rapamycin, drugs related to rapamycin (rapalogs), metformin, 17 a-estradiol, angiotensin converting enzyme inhibitors (and possibly angiotensin receptor blockers), flavonoids related to resveratrol, and aspirin and salsalate (Ferder et al 1993;Linz et al 1997Linz et al , 2000Basso et al 2007;Anisimov et al 2008Anisimov et al , 2010Anisimov et al , 2011Strong et al 2008;Harrison et al 2009Harrison et al , 2014Santos et al 2009;Smith et al 2010;Lamming et al 2013;Mercken et al 2014;Mitchell et al 2014). Metformin may even enhance survival in older humans (Bannister et al 2014).…”

Pharmacological induction of mitochondrial biogenesis as a therapeutic strategy for the treatment of type 2 diabetes

“…Several compounds structurally unrelated to resveratrol (e.g., SRT1720 and SRT2104) were described to selectively activate Sirt1 with a 1000-fold higher potency than resveratrol [145]. These compounds were highly effective at ameliorating insulin resistance in rodent models of diet-and genetically-induced obesity, in concert with the activation of the mitochondriogenic program [145,149,150]. However, the ability of these compounds to directly activate of Sirt1 has been questioned [151] and this concept is currently a matter of intense debate, although this does not directly undermine their potential therapeutic use.…”