Leonard GUARENTE, et al.
SIRT1 Polypeptides vs Aging
February 3, 2015
The Anti-Aging Pill
Facing a long wait for evidence, a
longevity researcher takes an unusual path to market
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
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,”
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
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.
21 February 2012
The Downside of Sirtuins
Proteins that boost longevity following dietary restriction
are also linked to anxiety
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
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
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
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
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.”
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.
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.
Methods for identifying agents that alter NAD-dependent
deacetylation activity of a SIR2 protein
SIRT1 Modulation of Adipogenesis and Adipose Function
CHOLESTEROL-REGULATING COMPLEX OF SIRT1 AND LXR AND METHODS
SIRTUIN BASED METHODS AND COMPOSITIONS FOR TREATING
US5874210 / WO9505459
Genes determining cellular senescence in yeast
Assays for compounds which extend life span
METHOD FOR SCREENING COMPOSITIONS
TRANSCRIPTION ADAPTORS IN EUKARYOTES
NO811973 / AT25985
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