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Sinclair says the finding also provides a plausible explanation for two well-known phenomena: that DNA damage accelerates aging, and that patterns of gene expression tend to go awry as an animal gets older.
The sirtuins have received considerable attention in recent years for their apparent role in aging. An overabundance of sirtuins extends the life spans of yeast, nematodes, and flies. In addition, molecules that seem to activate sirtuins--such as resveratrol, found in red wine--have a protective effect against some age-related diseases in mice. Sinclair cofounded Sirtris Pharmaceuticals in Cambridge, MA, to investigate the therapeutic possibilities of highly potent resveratrol-like molecules. The company is testing a series of products, including a treatment for treating type 2 diabetes.
The new study adds to this growing body of evidence for the many ways sirtuins contribute to aging and age-related disease. "SIRT1 is reported to do so many different things now; the challenge is going to be figuring out which of those it really does, and which of those are really important for diseases," says Brian Kennedy, another former member of Guarente's lab. Kennedy, now an associate professor of biochemistry at the University of Washington, was not involved in the study.
Guarente also emphasizes the broad importance of sirtuins, beyond the newly discovered SIRT1 mechanism. "The universal in aging we already know is sirtuins; they do so many things," he says. "The best way to approach this is to be able to trigger sirtuins so that you get all of the outputs and all of the benefits that they can bestow," he adds, noting that many of those outputs are unrelated to the new mechanism.
Sinclair and his colleagues also found evidence of a link between the SIRT1 mechanism and cancer, a disease strongly associated with old age. When dosed with resveratrol or beefed up with an extra copy of the SIRT1 gene, mice normally prone to cancer developed fewer tumors. Both of these interventions increased the available amount of SIRT1, likely enhancing the protein's ability to repair the DNA damage that leads to cancer without compromising its function as a gene regulator.
SIRT1 was already known to regulate a handful of mouse genes, but the new study revealed hundreds more. Many of these genes were found to be overexpressed in the brains of aging mice, underlining the potential importance of SIRT1-based gene deregulation in the aging process.
While the striking parallel between mice and yeast suggests that sirtuins' competing dual roles may be relevant in a wide variety of organisms, it remains to be seen just how that mechanism fits into the larger picture of mammalian aging, says Vijg. Nonetheless, Sinclair is confident that his group has uncovered a potentially universal mechanism. "Life, in general, has an Achilles heel," says Sinclair, "and this is it."
Healthier proteins may be the key to the long life span of naked mole rats.
Drugs much more powerful than the resveratrol found in red wine will be tested to treat diabetes.
A controversial biologist at Harvard claims he can extend life span and treat diseases of aging. He may be right.
Equally important as this fascinated research may be the question of why nature has not evolved fail-safes against this Sirt depletion (or, overuse of limited Sirt). It appears that each species is optimized with just enough Sirt regulation to ensure both reproduction of the species, and an optimum turnover of breeders. In other words, nature has found aging and death so practical that not only do we not find the ocassional immortal, but rather, we find an absolute universal death rate of one per customer.
Therefore, I would assume that the aging mechanism itself may have built-in redundancies to ensure that drastic life extension is unobtainable in nature, and no doubt extremely difficult even through science.
Evolution can't improve fitness of organism after it has reproduced, therefore it doesn't "see" death at all and many age related diseases get passed to offspring. I doubt that there is any special "aging mechanism" for whole organism (death of cell can actually be needed for survival of whole organism). For example, then car becomes rusty and breaks down with age, it is not because of some built in "aging mechanism", it just happens in absence of maintenance :).
Sirt1 aging process related to normal growth differentiation?
Two questions:
1) How does sirt1 know that dna damage has occured so that it drops its role as a gene stabilizer?
2) Could the sirt1 action of inhibiting some gene function be related to or a part of what causes/allows/engenders normal cell differentiation from blastomere onwards? ie Could this be part of a lifelong, growth to death process?
Re: Sirt1 aging process related to normal growth differentiation?
It doesn't appear as if this paper implicated Sirt1 as the protein that actually does the repair (though I may be wrong). It looks like Sirt1 just localizes to damaged regions. However, it was previously shown that Sirt1 deacetylates Ku70, a Non-homologous End Joining (NHEJ) repair protein. So Ku70 may cause Sirt1 to leave its DNA stabilization post. Alternatively, many signaling pathways exist to relay information about DNA damage and any number of these could feed into this Sirt1 activity. DNA damage sensors that lead to cell cycle arrest include ATM (Ataxia Telangiectasia Mutated) and ATR (ATM and Rad3-related). DNA damage sensors that lead to Nucleotide Excision Repair (NER) include XPC (Xeroderma Pimentosum Complementation, group C), CSA/CSB (Cockayne Syndrome A/B), hHR23a (human Homolog to Rad23 a), and RPA (Replication Protein A). In Double Stranded Break (DSB) repair, Rad52 initiates homologous recombination (HR). As mentioned earlier, Ku70 initiates NHEJ, a much more error prone mechanism of repairing DSB than HR. If Sirt1 indeed enhances Ku70 activity, this might cause NHEJ to be the favored mechanism (over HR), which has the potential to increase the number of mutations while allowing DNA damage to be repaired more quickly. You could see how this might have unpredictable effects on cell survival and senescence.
In response to your second question, Sirt1 for sure has an effect on cell cycle progression. It deacetylates and thereby inhibits p53, a mediator of apoptosis and cell cycle arrest. Sirt also activates FOXO, incresing the stress response, and inhibits NF-kB, decreasing inflammation. As far as differentiation, I doubt those Sirt-suppressed genes are involved in the differentiation of specific cell lineages, since Sirt activity is so general, but you may be on to something about them being anti-proliferation genes (since Sirt seems to be for the most part pro-proliferation).
http://www.sciencedaily.com/releases/2007/03/070313114146.htm
" Scientists have puzzled over just why organisms evolved aging as a strategy, and now there appears to be an answer. Allowing one individual to carry all the cellular damage inflicted over time, rather than dividing it between two organisms during reproduction, increases the chances that the individual's line will continue to reproduce for many generations to come, a new study indicates.
The earliest organisms, single-celled creatures called prokaryotes, which include bacteria, probably did not age but rather divided damaged material equally among new cells. There was not a parent cell, but rather the original cell divided into two siblings that were, in effect, the same age and shared the damage from the original cell equally.
Somewhere along the way, that strategy changed so that a parent cell retained most of the damage from aging and the offspring started with a mostly clean slate."
Thats true that the child starts with a "clean slate" - almost. Some DNA damage is passed on sometimes. For example older couples are far more likely to have a defective child, possibly because of DNA damage to the sperm or/and the egg. However if we could discover and replicate the mechanism whereby this is done, we could rejuvenate our bodies and reverse ageing. Much like reformatting our computers after the registry gets corrupted. If this is done carefully then we get a new computer and keep our old data.
In response to kitk, this argument has been going on for some time on TR (google "Aubrey de Grey Technology Review"). The most common argument against nature having "built-in" an aging mechanism is the bristlecone pine, which shows negligable senescence. Aging is an increase in the likelihood of dieing over time (mortality). There is no reason that this should have been built into a species, but there is also no reason for there to have evolved a mechanism of protection against it if reproduction can occur without this protection. It just happens, as memento said.
In response to tsaijohnhans, that is a really interesting article. I'm curious as to the mechanism by which cells keep their daughter cells relatively damage free. As for multi-cellular organisms like us, why can't our cell populations just use this mechanism to remain damage free indefinitely (that is the real question). I don't think the author of that article was correct to say that this study shows aging has evolved as a strategy. Rather, asymmetric damage distribution has evolved, and a sufficient repair mechanism has failed to evolve.
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Buyer beware on resveratrol
Since the Harvard resveratrol study on aging by Dr. Sinclair was published in the journal Nature a flood of dubious companies have sprung up selling resveratrol. Many have no scientist, no labs, no quality control and no experience. Dr. Oz recommends Biotivia Bioforte and Transmax. Consumer Lab, an independent testing authority, evaluated the major brands and found many lacking in content and quality. The highest potency products that passed their evaluation were Biotivia, Transmax and Bioforte. A product by Life Extension Co. failed badly with only 26% of the claimed resveratrol. Another brand, Revatrol, had virtually no trans-resveratrol in its supplement. Revgenitics refused to provide samples for testing. The ConsumerLab test results are available on their web site.
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