SIRT1 studies

[Guest guest]

Hi All,

It had been observed that Has anyone happened on this press release

from the Guarente lab at MIT? Optimism is expressed for targeting SIR-

1 with drugs in order to trigger the body's CR response without

actually demanding calorie reduction.

http://web.mit.edu/newsoffice/2004/aging.html

See also:

``Genetic Studies: Calorie Restriction a Boost to Longevity''

- http://www.moremusic104.com/index.php?nid=115 & sid=23854

This refers to the article:

Gene Links Calorie Deprivation and Long Life in Rodents

Couzin, Science 18 June 2004: 1731.

http://calorierestriction.org/pmid/?n=15205503 [NO ABSTRACT WORTH

MENTIONING]

and to:

``Calorie Restriction Promotes Mammalian Cell Survival by Inducing

the SIRT1 Deacetylase''

- http://calorierestriction.org/pmid/?n=15205477

The one-page review by Couzin adds new concepts into the discussion

on whether or not the SIRT1 studies will lead to longer human life.

As Matt Kaeberlein suggests, it is some distance from cells living in

culture to human beings. The below is the article cited above from

Science.

Couzin J.

Research on aging. Gene links calorie deprivation and long life in

rodents.

Science. 2004 Jun 18;304(5678):1731. No abstract available.

PMID: 15205503 [PubMed - indexed for MEDLINE]

Slashing calories extends life in nearly every species tested in

the lab--but how? Now two researchers in the field of aging--a

veteran molecular biologist at the Massachusetts Institute of

Technology (MIT) and his former postdoctoral fellow--have published

papers independently delineating the effects in rodents of a gene

associated with aging and influenced by diet.

The discovery grows out of research by Leonard Guarente and

colleagues at MIT, who found a yeast gene, SIR2, that appeared to

mediate low glucose and to slow aging when calories were cut. The

group then found a similar gene in mice, SIRT1, and checked to see if

had parallel effects.

Research by both Guarente and his former postdoc Sinclair,

now based at Harvard Medical School in Boston, suggests that the

parallel is real. And competition between the two groups may have

speeded their discoveries: " It's the kind of work that you assumed

would be done 3 or 4 years from now, " says , a

biogerontologist at the University of Michigan, Ann Arbor.

Sinclair's paper, published online this week by Science

(www.sciencemag.org/cgi/content/abstract/1099196), examines how cells

survive when SIRT1 levels change. It's long been known that cells

from calorically restricted animals are resistant to apoptosis, a

programmed cell death. Sinclair wondered if SIRT1 had a hand in this.

First, his lab and collaborators at the National Institute on

Aging in Bethesda, land, studied rats on low-calorie diets. Their

brain, liver, kidney, and fat tissue all showed levels of SIRT1

protein at least 50% above normal. Next, Sinclair's team collected

human cells and immersed them in serum from the calorically

restricted rats. The serum forced an uptick in SIRT1 levels and

protected the cells from apoptosis.

Sinclair then guessed that two key players were insulin and an

insulin growth factor. Both are lowered in calorie-restricted

animals. Adding either one to the mix blunted the serum's effects,

making the human cells express less SIRT1. Furthermore, his group

found, excess SIRT1 represses a critical initiator of apoptosis--a

protein called Bax, which punches holes in a cell's mitochondria and

induces cell death.

Figure:

Suspect. By blocking growth of fat cells such as these in mice,

the SIRT1 gene may extend life.

CREDIT: FREDERIC PICARD AND LEONARD GUARENTE

Guarente, meanwhile, focused on another piece of the SIRT1 puzzle:

fat, which long-lived, calorically restricted animals lack. First,

his group looked at mouse cells that, if left alone, would

differentiate into fat cells. Overexpressing SIRT1, the researchers

found, stopped them from turning into fat. In addition, high doses of

SIRT1 forced cells that had already differentiated into fat- storing

adipocytes to shed fat. SIRT1 also blunted a key protein, PPAR-, that

activates fat-storage genes.

The findings held up in mice: Genes that spur fat accumulation

were repressed in animals after an overnight fast. The SIRT1 protein

had latched itself onto promoters of those genes, hindering their

activity, the researchers reported online in Nature on 3 June. It's

not clear why reducing fat would extend life, although mice

engineered to have less of it live longer.

The work shows that " genes that regulate fat cell development and

mobilization ... are under the control of SIRT1, " says Verdin, a

molecular biologist at the Gladstone Institute of Virology and

Immunology at the University of California, San Francisco. Both

papers, he adds, are " truly beautiful. "

But they're just the first pieces of an intricate puzzle, Verdin

adds. Most biologists assume that SIRT1 has other effects, and " it's

become really hard to figure out [their] relative importance, " says

Matt Kaeberlein, a molecular biologist at the University of

Washington, Seattle. Sinclair and others also note that SIRT1's

activities in a petri dish may not mirror what it does in an animal.

That hasn't stopped Sinclair and Guarente from dreaming about

SIRT1-based drugs that might combat obesity or extend life. Elixir

Pharmaceuticals, a Cambridge, Massachusetts-based biotechnology

company co-founded by Guarente, holds a license on SIRT1 and some of

its targets.

Al Pater