Tag Archives: sirtuin

Aging successfully reversed in mice – human trials to start next

As incredible as it may sound, scientists have successfully reversed the aging process in mice, according to a new study published in Cell.

Reversing aging, a real possibility?

Many of the chronic diseases that exist in older adults constitute a highly significant social and economic burden to the community; if you think about it, eliminating (or at least alleviating) the effects of aging means not only increasing the lifespan, but also increasing the life quality and reducing health costs… it could pave the way for a new world. But can this really be done, or is it merely wishful thinking?

Lead researcher David Sinclair of the University of New South Wales and his team showed that at least in mice, it’s not only possible – it’s already been done. After administering a certain compound to the mice, muscle degeneration and diseases caused by aging were reversed, with surprisingly successful results:

“I’ve been studying aging at the molecular level now for nearly 20 years and I didn’t think I’d see a day when ageing could be reversed. I thought we’d be lucky to slow it down a little bit. The mice had more energy, their muscles were as though they’d be exercising and it was able to mimic the benefits of diet and exercise just within a week. We think that should be able to keep people healthier for longer and keep them from getting diseases of ageing.”, Sinclair said.

sirtuin

The compound in case is Sirtuin 1 (SIRT1), one of seven mammalian sirtuins, known for playing an important role in metabolic homeostasis (the process of regulating and stabilizing metabolism). Generally speaking, sirtuins are a class of proteins which regulate many important biological pathways – they have been linked to longevity before. The trick here was to stimulate communication between the mitochondria and the cell nucleus, with the compound the increasing the level of a naturally occurring substance in the human body called nicotinamide adenine dinucleotide. This substance decreases as people age, though not as much in people who exercise and follow a healthy diet.

The compound that the mice ate had fast, remarkable results; their muscles became toned, as if they’d been exercising. Inflammation, a key factor in many disease processes, was drastically reduced. Insulin resistance also declined dramatically and the mice had much more energy overall. The process was absolutely amazing – scientists compared it to a 60 year old having the muscle fitness and overall stamina of a 20 year old. But to make this even more amazing – it all took just one week! It almost sounds too good to be true, which brings us to the next issue…

Why isn’t this the biggest news?

David Sinclair.

The thing is, this research was funded before… sort of. Sirtris, a company developed by Sinclair was owned by GlaxoSmithKline, and human trials were set to start for this very treatment. However, a big research team from the Institute of Healthy Ageing at the University College of London published an article in Nature saying that the underlying mechanism was bogus, and that Sinclair’s initial results were simply experimental flaw. The study received good reviews, and was generally approved by the scientific community. All funding was pulled, and the project was killed, leaving Sinclair discredited.

But he pulled on! He kept going, and with this study, he proves that the underlying mechanism was right all along. It is a sad story of science doing the right thing and double checking, which only resulted in delaying something which seems to be a monumental discovery. But even now, investors are likely hesitant to invest in his project.

Even as aging was successfully reversed in mice, Sinclair says he needs to raise more money before he can commit to a date when trials may begin in humans. Hopefully, his efforts won’t be in vain.

Scientific Reference: http://dx.doi.org/10.1016/j.celrep.2014.01.031
2014 Sinclair at TEDX Sydney 

Representative photographs from blinded histopathological analysis of kidney, liver, and lung panels for mice on standard diet (SD) and SRT1720 supplementation (credit: Sarah J. Mitchell et al./Cell Reports)

Sirtuin supplement diet prolongs life in mice

A wonder pill that prolongs life and cuts the risks of developing deadly diseases. Scientists have been looking for such a drug for a long time. Research in this direction shows that enhancing the expression of a certain gene called SIRT1 (sirtuin 1) may fare good results in this respect. Recently, researchers at the National Institute on Aging at the National Institutes of Health  report that after feeding mice with sirtuin supplements their lives were significantly prolonged and showed better health than the control group of mice.

Sirtuin 1, or SIRT1, is known to play an important role in maintaining metabolic balance in multiple tissues, and studies in various organisms have shown that activating the protein can lead to many health benefits. Additionally, the NIANIH scientists report in the Cell Press journal that expression of SIRT1 is also associated with  the delay of age-associated diseases in several animal models.

Representative photographs from blinded histopathological analysis of kidney, liver, and lung panels for mice on standard diet (SD) and SRT1720 supplementation (credit: Sarah J. Mitchell et al./Cell Reports)

Representative photographs from blinded histopathological analysis of kidney, liver, and lung panels for mice on standard diet (SD) and SRT1720 supplementation (credit: Sarah J. Mitchell et al./Cell Reports)

Dr. Rafael de Cabo  along with colleagues fed mice beginning at 6 months of age with a diet containing  a small molecule that activates SIRT1, called SIRT1720,  for the remainder of their lives. It was found that SIRT1720 significantly extended the average lifespan of mice by 8.8%. In addition, the  100 mg/kg SRT1720 diet also reduced body weight and body fat percentage, and it improved muscle function and motor coordination throughout the animals’ lives.

Besides the beneficial metabolic effects,  SRT1720 supplementation led to decreases in total cholesterol and LDL-cholesterol levels, which might help protect against heart disease, and improvements in insulin sensitivity, which could help prevent diabetes.  The supplement was also found to be effective against tissue inflammation, yet again backing it longevity properties since low-grade chronic inflammation is thought to contribute to aging and age-related diseases.

“Here, we show for the first time that a synthetic SIRT1 activator extends lifespan and improves healthspan of mice fed a standard diet,” says Dr. de Cabo. “It illustrates that we can develop molecules that ameliorate the burden of metabolic and chronic diseases associated with aging.”

Like I said before, though, sirtuin is no new player in the longevity game. Two years ago, I wrote about the developments at the time concerning sirtuin research. No particular connection to enhanced  lifespan from SIRT1 in fruit flies or nematodes was discovered, but tests on mammals hadn’t been made yet.

What’s more interesting maybe is that researchers at Bar-Ilan University in Ramat-Gan, Israel chose to take an alternate route, yet still in the sirtuin family – SIRT6. Instead of feeding them supplements, the Israeli researchers engineered mice that overexpressed SIRT6 and found male mice median lifespan  rose by 14.5% in one line of their transgenic mice and 9.9% in another. When maximum life span is concerned, the metric rose by 15.8% in the first line of mice, and 13.1% in the second. Curiously enough, there weren’t any signaled differences in lifespan for female mice.

mice longevity gene

Sirtuin back in the highlight as longevity gene – overexpression prelongs male mice lifespan by 15%

For a number of years now researchers have been studying the sirtuin gene and the proteins encoded in it as it is believed to be directly linked to prolonged lifespan. A myriad of individual studies were performed with mixed results, and so far hundreds of millions have been allocated for research in this direction. A certain company has actually leaped ahead and advertised cosmetic products on the market which allegedly stimulate an enhanced expression of the gene, despite the scientific community hasn’t generally concluded that sirtuin may lead to a prolonged life.

It all began when a link between the sirtuin gene in yeast and maximum lifespan was observed, and since then scientists all over the world have been paying very close attention to it. To try to see if it might impact human lifespan as well, scientists have almost universally direct their attention towards SIRT1, another member of the sirtuin gene family, which is expressed in mammals and most closely related to the yeast longevity gene. Biotech companies have invested a lot of money in sirtuin research, with many boosting impressive results. Most recently, however, scientists have begun to question its longevity link. With this in mind, a group of researchers demonstrated that sirtuin has no particular connection to enhanced lifespan fruit flies or nematodes, as previously reported on ZME Science. Moreover, absolutely no effect of SIRT1 on longevity in mammals has been reported as of yet, although it’s been associated with a healthier metabolism in mice fed a high-fat die, and thus longer life.

Looking elsewhere in the sirtuin family

mice longevity gene Another member of the sirtuin gene family, SIRT6, looks a lot more interesting, however. While all efforts are concentrated on SIRT1, molecular biologist Haim Cohen of Bar-Ilan University in Ramat-Gan, Israel chose to have a different look towards a much more obscure route. “People were mostly interested in SIRT1,” he says. “So I thought it might be better for us as a new lab to work on something that is less crowded.”

Cohen’s research and interest proved to pay off, eventually. A previous research from 2006 observed how mice lacking SIRT6 were sickly, small, and with a reduced ability of repairing damaged DNA – these mice died within a month. Cohen wanted to see what would happen if the opposite were to occur, and had a strain of mice express higher levels of SIRT6 than normal. What he found was that male mice median lifespan  rose by 14.5% in one line of their transgenic mice and 9.9% in another. When maximum life span is concerned, the metric rose by 15.8% in the first line of mice, and 13.1% in the second. Curiously enough, there weren’t any signaled differences in lifespan for female mice.

The missing genetic link to longevity? Not so fast…

“It’s a good bet that each of the sirtuins does something interesting,” says Richard Miller, who studies ageing at the University of Michigan in Ann Arbor. “But the case for whether any one of them is important to ageing and longevity in mammals is somewhat weak and circumstantial.”

Miller makes reference to the fact that the particular strain of mice used in the research is prone to a cancerous tumor, most evident in males. It’s possible that SIRT6 might have an anti-cancer effect. What about the clear difference between the female and male mice? Female mice were found to live in the strain were found live 15% more than male, prior to SIRT6 treatment. Cohen speculates that the male mice inflicted with the hyperactive gene caught up with the female mice, as SIRT6 is mimicking effects already seen in the females.

Also it’s important to note whether SIRT6 addresses any improvements in clear aging conditions, like cataract formation and declines in memory and mobility, even cell degradation. It might just improve the metabolism. The fact remains, however, that the study, still in its infancy, is of extreme interest, and prove to an extent that all this focus may not have been in vain after all. There other genes in the sirtuin family which haven’t been granted the necessary attention, and those as well might show some promising results.

“People are just beginning to come to grips with the fact that there are seven sirtuins and each may do different things,” says Miller. “The quicker people stop thinking in terms of ‘it’s either gold or tin’ and start addressing the nuances of sirtuin function, the better.”

The results were published in the journal Nature.

Illustration credit

‘Longevity gene’ debunked – there’s no such thing

Scientists from the UK and Hungary have run various experiments to verify the claim of US researchers that a certain gene is responsible for the increase of lifespan, as shown in some test organisms. Their results show, in fact, that the so called “longevity gene” allegedly responsible for the generation of an anti-aging protein doesn’t affect longevity at all.

The round­worm C. ele­gans, used in some ag­ing studies. (c) Wikimedia Commons, National Human Genome Research Institut

The round­worm C. ele­gans, used in some ag­ing studies. (c) Wikimedia Commons, National Human Genome Research Institut

The substance controlled by the gene, called sirtuin, has since been the subject of heavy marketing campaigns by cosmetic companies who advertised sirtuin enhancing anti-aging products, like anti-wrinkle creams or anti-aging pills.

The initial research which came with the longevity gene conclusion based their work on the study of yeast, nem­a­tode worms and fruit flies, of­ten used as mod­els for the bi­ol­o­gy of hu­man aging. Their initial conclusion was that when the or­gan­is­ms over­pro­duced sir­tuin, they lived long­er, by as much as 50 per­cent in the case of nem­a­todes. Another connection to increased lifespan was found to be dietary restrictions, which scientists claimed stimulated the production of sirtuins.

A subsequent research, however, published in this week’s edition of the jour­nal Na­ture, led by Da­vid Gems and col­leagues at Uni­vers­ity Col­lege Lon­don, shows that there isn’t any conclusive evidence that links sirtuin to enhanced lifespan.

“These re­sults are very sur­pris­ing. We have re-ex­am­ined the key ex­pe­ri­ments link­ing sir­tuin with longe­vity in an­i­mals and none seem to stand up to close scru­ti­ny. Sir­tu­ins, far from be­ing a key to longe­vity, ap­pear to have noth­ing to do with ex­tending life,” Gems said. “But I think this is good news in a way: af­ter all, re­vis­ing old ideas can be as im­por­tant as pre­sent­ing new ones to as­sure sci­en­tif­ic prog­ress. This work should help to re­di­rect sci­en­tif­ic ef­forts to­ward those pro­cesses that really do con­trol age­ing.”

Re­search­ers at the Uni­vers­ity of Wash­ing­ton, Se­at­tle, and Sem­mel­weis Uni­vers­ity, Bu­da­pest, ex­am­ined two strains of nem­a­tode worm, each from a dif­fer­ent pri­or stu­dy. These were ma­ni­pu­lated to have a hy­per­ac­tive sir­tuin gene to that the hypothesis might be tested. The nematode indeed was initially found to live longer, but subsequent tests showed that after living conditions were made the same for both normal and genetically-enhanced worms, that there wasn’t any considerable difference in lifespan which could’ve been attributed to sirtuin. Suspecting that some other genetic factor must have caused the longevity, they identified a mutation in a gene involved in the development of nerve cells as the cause.

In the case of the fruit-fly, were considerable longevity was also reported, scientists actually engineered a new strain of fruit fly, Dro­soph­i­la melanogaster, which could hyper-actively generate sirtuin. They found no reason to consider the new strain particularly long-lived.

Finally, the dietary restriction was also put to the test. ak­ing mu­tant fruit flies that lacked the sir­tuin gene, the re­search­ers showed that di­e­tary re­stric­tion still in­creased life­span. So di­e­tary re­stric­tion was work­ing in­de­pend­ently of sir­tu­ins.

All those sirtuin-based creams and pills are nothing but expensive placebos.