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
byAnne 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
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
