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Leonard GUARENTE, et al.

SIRT1 Polypeptides vs Aging









http://www.technologyreview.com/news/534636/the-anti-aging-pill/?utm_source=outbrain&utm_medium=content&utm_term=longevity&utm_content=fastandMIT&utm_campaign=june2015
February 3, 2015

The Anti-Aging Pill

Facing a long wait for evidence, a longevity researcher takes an unusual path to market

By

Karen Weintraub

Why It Matters

Everyone is getting older. Few are happy about it.

An anti-aging startup hopes to elude the U.S. Food and Drug Administration and death at the same time.

The company, Elysium Health, says it will be turning chemicals that lengthen the lives of mice and worms in the laboratory into over-the-counter vitamin pills that people can take to combat aging.

The startup is being founded by Leonard Guarente, an MIT biologist who is 62 (“unfortunately,” he says) and who’s convinced that the process of aging can be slowed by tweaking the body’s metabolism.

The problem, Guarente says, is that it’s nearly impossible to prove, in any reasonable time frame, that drugs that extend the lifespan of animals can do the same in people; such an experiment could take decades. That’s why Guarente says he decided to take the unconventional route of packaging cutting-edge lab research as so-called nutraceuticals, which don’t require clinical trials or approval by the FDA.

This means there’s no guarantee that Elysium’s first product, a blue pill called Basis that is going on sale this week, will actually keep you young. The product contains a chemical precursor to nicotinamide adenine dinucleotide, or NAD, a compound that cells use to carry out metabolic reactions like releasing energy from glucose. The compound is believed cause some effects similar to a diet that is severely short on calories — a proven way to make a mouse live longer.

Elysium’s approach to the anti-aging market represents a change of strategy for Guarente. He was previously involved with Sirtris Pharmaceuticals, a high-profile biotechnology startup that studied resveratrol, an anti-aging compound found in red wine that it hoped would help patients with diabetes. That company was bought by drug giant GlaxoSmithKline, but early trials failed to pan out.

This time, Guarente says, the idea is to market anti-aging molecules as a dietary supplement and follow up with clients over time with surveys and post-marketing studies. Guarente is founding the company along with Eric Marcotulli, a former venture capitalist and technology executive who will be CEO, and Dan Alminana, chief operating officer.

The company says it will follow strict pharmaceutical-quality production standards and make the supplements available solely through its website, for $60 for a 30-day supply or $50 per month with an ongoing subscription.

“You have high-end prescription drugs up here, which are expensive,” says Guarente, gesturing upward. “And you have the nutraceuticals down there, which are a pig in a poke — you don’t know what you’re getting and you don’t know a lot about the science behind them. There’s this vast space in between that could be filled in a way that’s useful for health maintenance.”

An anti-aging pill with an ivory-tower pedigree could prove profitable. The $30 billion supplements market is growing at about 7 percent a year overall, Alminana says, and at twice that rate for online sales.

Elysium declined to name its investors, but it has some high-level endorsements. Its board includes Daniel Fabricant, former director of the FDA’s division of dietary supplements and now CEO of the Natural Products Association, a trade association. The company also has five Nobel Prize winners advising it including neuroscientist Eric Kandel, biologist Thomas Südhof, origin-of-life theorist Jack Szostak, and the 2013 laureate in chemistry Martin Karplus.

Karplus, now an emeritus professor at Harvard, said in a telephone interview that he was turning 85 this year and had asked the company to send him a supply of Basis as soon as it’s available. “I want to remind myself whether I really want to take it or not,” says Karplus.

Scientists have shown they can reliably extend the life of laboratory mice by feeding them less, a process known as “caloric restriction.” That process seems to be mediated by biological molecules called sirtuins. NAD is important because it’s a chemical that sirtuins need to do their work and is also involved in other aspects of a cell’s metabolism. In worms, mice, and people, NAD levels fall with age, says Guarente, so the idea is to increase levels of the molecule.

“NAD replacement is one of the most exciting things happening in the biology of aging,” says Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, who has coauthored scientific papers with Guarente but is not involved in Elysium. “The frustration in our field is that we have shown we can target aging, but the FDA does not [recognize it] as an indication.”

Other experts said while NAD may decline with age, there is limited evidence that aging can be affected by restoring or increasing NAD levels. “There is enough evidence to be excited, but not completely compelling evidence,” said Brian K. Kennedy, CEO of the California-based Buck Institute for Research on Aging.

Guarente says Elysium’s pill includes a precursor to NAD, called nicotinamide riboside, which the body can transform into NAD and put to use. In addition, the pill contains pterostilbene, an antioxidant that Guarente says stimulates sirtuins in a different way. Both ingredients can already be found in specialty vitamins.  “We expect a synergistic effect [from] combining them,” he says.

Guarente says Elysium plans to gradually add to its product line with other compounds shown in academic labs to extend the healthy lifespan of worms, mice, or other animals. The company will do preliminary testing to make sure the products are not toxic but will not follow the arduous FDA approval process. Vitamins and supplements can be sold over the counter as long as they contain ingredients known to be safe and don’t make overly specific health claims.

Marcotulli says the company has some anecdotal evidence that Elysium’s pills make a difference. “For older demographics, we’ve heard really interesting feedback related to levels of energy. It’s very, very useful and restorative,” he says. And he takes the pills himself. “When I don’t have a supply, I feel actually fuzzy,” he said. “It’s become a staple of my routine.”

Guarente also says he takes Basis every day, along with 250 mg of resveratrol, the red-wine compound. Guarente also exercises — though not, he says, as often as he should.

He says it doesn’t trouble him that he sees no obvious benefits yet from his supplement regimen. Too many studies in the anti-aging field, he says, are too short-term to show real benefits. Or else they study people who are already unhealthy. “I think that’s the way it would be if something is really acting to slow your progression into decrepitude — you’re not going to notice that,” Guarente says.





http://www.elysiumhealth.com/

(888) 220-6436



http://www.technologyreview.com/article/426953/the-downside-of-sirtuins/
21 February 2012

The Downside of Sirtuins

Proteins that boost longevity following dietary restriction are also linked to anxiety

by

Anne Trafton

Over the past decade, MIT biologist Leonard Guarente ‘74 and others have shown that very low-calorie diets provoke a comprehensive physiological response that promotes survival, all orchestrated by a set of proteins called sirtuins.

Now, Guarente and colleagues have shown that sirtuins are also likely to play a key role in the psychological response to dietary restriction. When sirtuins are elevated in the brain, as occurs when food intake is cut, serotonin levels drop in mice and the animals become much more anxious. Furthermore, in two large genetic studies of humans, the team found that mutations that boost production of sirtuins are commonly associated with higher rates of anxiety and panic disorder.

The researchers believe this anxiety may be an evolutionary adaptation that makes animals—including humans—more cautious under the stress of having to forage more widely for scarce food.

“It makes sense, because behavioral effects would be as adaptive, and as selected by evolution, as physiological effects,” says ­Guarente, a professor of biology. “I don’t think it’s surprising that behavior really falls under the umbrella of natural selection.”

Guarente discovered about 20 years ago that sirtuins prolong life span in yeast; since then, they have been shown to have similar effects in worms, mice, and other animals. Normally turned on in response to stresses such as starvation or inflammation, the compounds coördinate a variety of hormonal networks, regulatory proteins, and genes, with a net effect of keeping cells alive and healthy.

His new research, published online in Cell in December, examined mice with elevated levels of the SIRT1 protein in their brains and mice with no SIRT1. Researchers placed them on a circular raised platform with two quadrants protected by a wall and two unprotected quadrants. “Normal mice will spend a considerable amount of time venturing out into the unprotected region, and super-anxious mice tend to stay in the protected area,” Guarente says.

The mice with very high sirtuin levels spent much more time closer to the walls, suggesting that they were more anxious. Mice lacking sirtuin were much more adventuresome.

The team investigated the cellular mechanism behind this phenomenon. They found that sirtuins help control levels of the neurotransmitter serotonin, long known to be critical for mood regulation.

The new research suggests that anxiety could be treated with drugs that inhibit sirtuins. But it also offers reason for caution when treating patients with drugs that activate sirtuins, several of which are now in clinical trials for diabetes and other metabolic diseases. Those drugs can’t enter the brain, but some researchers are exploring the possibility of using sirtuin activators to treat neurological disorders such as Alzheimer’s disease. If such drugs were developed and approved, doctors might need to watch for anxiety as a possible side effect.

“We want to learn as much as we can about the biology of sirtuins, to inform the use of sirtuin drugs to treat diseases,” Guarente says. “The more we know about the biology, the better position we’ll be in to know how to use the drugs, how to dose them, and how to anticipate any possible side effects.”



https://www.youtube.com/watch?v=_QUgyxDs1oc

NAD Reversal



Patents

US2005164969
Method of extending life span


The present invention provides new and advantageous methods, compositions, cell constructs and animal models related to inhibiting the senescence of vertebrate cells and vertebrate organisms based on the use of SIRT1 polynucleotides and polypeptides, as well as mutant SIRT1 polynucleotides and polypeptides. The invention provides polynucleotides that encode variants and fragments of SIRT1 polypeptides, and also provides variant SIRT1 polypeptides and fragments thereof. Additionally the invention provides a method of inhibiting or delaying the expression in a vertebrate cell of a protein having biological activity associated with loss of population doubling in the cell. The invention further provides a method of treating a pathology, a disease or a medical condition in a subject, wherein the pathology responds to an SIRT1 polypeptide. The invention also provides a vertebrate cell that incorporates a heterologous nucleic acid encoding a variant of SIRT1, or a fragment thereof, as well as a transgenic mammal a majority of whose cells harbor a transgene including a nucleic acid sequence encoding an SIRT1 polypeptide. The invention also provides an antibody that binds immunospecifically to a variant SIRT1 polypeptide or a fragment thereof, and a method of determining whether the amount of an SIRT1 polypeptide in a sample differs from the amount of the SIRT1 polypeptide in a reference. The invention further provides a method of contributing to the diagnosis or prognosis of, or to developing a therapeutic strategy for, a disease or pathology in a subject, wherein the disease or pathology responds to treatment with an SIRT1 polypeptide and wherein the amount of SIRT1 polypeptide in the pathology is known to differ from the amount of the SIRT1 polypeptide in a nonpathological state.







US8652797
METHODS FOR IDENTIFYING AGENTS WHICH ALTER HISTONE PROTEIN ACETYLATION, DECREASE AGING OR INCREASE LIFESPAN


Methods of identifying agents which alter the NAD-dependent acetylation status and mono-ADP-ribosylation of nuclear proteins are disclosed. The methods further include identifying agents which alter the life span or aging of a cell or an organism by determining the level of NAD-dependent acetylation and/or ADP ribosylation of a nuclear protein. The invention also relates to a mammalian Sir2 protein which acetylates or deacetylates nuclear proteins in a NAD-dependent manner and has mono-ADP-ribosyltransferase activity. Host cells producing the Sir2 protein and antibodies to the Sir2 protein are also provided.

   



US8642284
Methods for identifying agents that alter NAD-dependent deacetylation activity of a SIR2 protein

US8546090
SIRT4 ACTIVITIES

US8546074
SIR2 ACTIVITY

US2011218229
SIRT1 Modulation of Adipogenesis and Adipose Function
     
WO2007146023
CHOLESTEROL-REGULATING COMPLEX OF SIRT1 AND LXR AND METHODS OF USE

US2011009474
SIRTUIN BASED METHODS AND COMPOSITIONS FOR TREATING BETA-CATENIN-RELATED CONDITIONS

US5874210 / WO9505459
Genes determining cellular senescence in yeast

US2004005574
SIR2 activity

US6228583
Assays for compounds which extend life span

WO9402588
METHOD FOR SCREENING COMPOSITIONS

WO9310250
TRANSCRIPTION ADAPTORS IN EUKARYOTES

WO03004621
SIR2 ACTIVITY

NO811973 / AT25985
Plasmid

IT1144705
Polypeptide production

CA2519161
SIR2 ACTIVITY





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